Combination pharmaceutical agents as rsv inhibitors

ABSTRACT

The present invention relates to pharmaceutical agents administered to a subject either in combination or in series for the treatment of a Respiratory Syncytial Virus (RSV) infection, wherein treatment comprises administering a compound effective to inhibit the function of the RSV and an additional compound or combinations of compounds having anti-RSV activity.

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.62/566,159, filed on Sep. 29, 2017, and U.S. Provisional Application No.62/566,160, filed on Sep. 29, 2017. The entire teachings of the aboveapplications are incorporated herein by reference.

TECHNICAL FIELD

The present invention relates generally to compounds and pharmaceuticalcompositions useful as Respiratory Syncytial Virus (RSV) inhibitors.Specifically, the present invention relates to benzodiazepinederivatives that can be used in combination with other pharmaceuticalagents for treating RSV infection.

BACKGROUND OF THE INVENTION

Human respiratory syncytial virus (HRSV) is a negative-sense, singlestranded, RNA paramyxovirus (KM. Empey, et al., Rev. Anti-InfectiveAgents, 2010, 50(1 May), 1258-1267). RSV is the leading cause of acutelower respiratory tract infections (ALRI) and affects patients of allages. The symptoms in adults are usually not severe and are typicallyanalogous to a mild cold. However, in infants and toddlers the virus cancause lower respiratory tract infections including bronchiolitis orpneumonia with many of them requiring hospitalization. Nearly allchildren have been infected by age 3. There are known high-risk groupsthat infection with RSV is more likely to progress into the ALRI.Premature infants and/or infants suffering from lung or cardiac diseaseare at the highest risk to develop ALRI. Additional high-risk groupsinclude the elderly, adults with chronic heart and/or lung disease, stemcell transplant patients and the immunosuppressed.

Currently, there is no vaccine available to prevent HRSV infection.Palivizumab is a monoclonal antibody that is used prophylactically toprevent HRSV infection in high risk infants, e.g. premature infants, andinfants with cardiac and/or lung disease. The high cost of palivizumabtreatment limits its use for general purposes. Ribavirin has also beenused to treat HRSV infections but its effectiveness is limited. There isa major medical need for new and effective HRSV treatments that can beused generally by all population types and ages.

There have been several RSV fusion inhibitors that have been disclosedin the following publications: WO2010/103306, WO2012/068622,WO2013/096681, WO2014/060411, WO2013/186995, WO2013/186334, WO2013/186332, WO2012/080451, WO2012/080450, WO2012/080449, WO2012/080447,WO2012/080446, and J. Med. Chem. 2015, 58, 1630-1643. Examples of otherN-protein inhibitors for treatment of HRSV have been disclosed in thefollowing publications: WO 2004/026843, J. Med. Chem. 2006, 49,2311-2319, and J. Med. Chem. 2007, 50, 1685-1692. Examples of L-proteininhibitors for HRSV have been disclosed in the following publications:WO2011/005842, WO2005/042530, Antiviral Res. 2005, 65, 125-131, andBioorg. Med. Chem. Lett. 2013, 23, 6789-6793. Examples ofnucleosides/polymerase inhibitors have been disclosed in the followingpublications: WO2013/242525 and J. Med. Chem. 2015, 58, 1862-1878.

There is a need for the development of effective treatments for HRSV.The present invention has identified compounds that are aminoheteroarylsubstituted benzodiazepines, and inhibit HRSV. The invention includesmethods to prepare the compounds as well as methods of using thesecompounds to treat disease.

SUMMARY OF THE INVENTION

The present invention provides compounds represented by Formula (I), andpharmaceutically acceptable salts, esters or prodrugs thereof that canbe used to treat or prevent viral (particularly HRSV) infection:

wherein:R₁ is selected from the group consisting of:

1) Hydrogen;

2) Halogen;

3) CN;

4) Optionally substituted —C₁-C₈ alkyl; and

5) Optionally substituted —C₁-C₈ alkyl —O—R₁₁;

R₂ and R₅ are each independently selected from the group consisting of:

1) Hydrogen; and

2) Optionally substituted —C₁-C₈ alkyl;

A is selected from the group consisting of:

1) Optionally substituted —C₃-C₁₂ cycloalkyl;

2) Optionally substituted —C₃-C₁₂ cycloalkenyl;

3) Optionally substituted 3- to 12-membered heterocycloalkyl;

4) Optionally substituted aryl; and

5) Optionally substituted heteroaryl;

R₃ is hydrogen or R₁₁;R₄ is selected from the group consisting of:

1) Hydrogen;

2) Optionally substituted —C₁-C₈ alkyl;

3) Optionally substituted —C₂-C₈ alkenyl;

4) Optionally substituted —C₂-C₈ alkynyl;

5) Optionally substituted —C₃-C₁₂ cycloalkyl;

6) Optionally substituted —C₃-C₁₂ cycloalkenyl;

7) Optionally substituted 3- to 12-membered heterocyclyl;

8) Optionally substituted aryl;

9) Optionally substituted heteroaryl;

10) —NR₁₃R₁₄;

11) —CO—NR₁₃R₁₄; and

12) —SO₂—NR₁₃R₁₄;

Each R₆ is the same or different and independently selected fromhalogen, hydroxyl, protected hydroxyl, cyano, amino, protected amino,nitro, optionally substituted —C₁-C₈ alkyl, optionally substituted—C₁-C₈ alkoxy, optionally substituted —NHC₁-C₈ alkyl, optionallysubstituted —S—(—C₁-C₈ alkyl), optionally substituted —SO₂—(—C₁-C₈alkyl), optionally substituted —SO₂—NH—(—C₁-C₈ alkyl), optionallysubstituted —NH—SO₂—(—C₁-C₈ alkyl), —CO₂R₁₂, and —NR₁₃R₁₄, and—CO—NR₁₃R₁₄;R₁₁ and R₁₂ are each independently selected from the group consistingof:

1) Optionally substituted —C₁-C₈ alkyl;

2) Optionally substituted —C₂-C₈ alkenyl;

3) Optionally substituted —C₂-C₈ alkynyl;

4) Optionally substituted —C₃-C₈ cycloalkyl;

5) Optionally substituted —C₃-C₈ cycloalkenyl;

6) Optionally substituted 3- to 8-membered heterocycloalkyl;

7) Optionally substituted aryl; and

8) Optionally substituted heteroaryl;

R₁₃ and R₁₄ are each independently selected from hydrogen, optionallysubstituted —C₁-C₈-alkyl, optionally substituted —C₂-C₈-alkenyl,optionally substituted —C₂-C₈-alkynyl; optionally substituted—C₃-C₈-cycloalkyl, optionally substituted —C₁-C₈-alkoxy, —C(O)R₁₂,—S(O)₂R₁₂, and —S(O)₂NHR₁₂; alternatively, R₁₃ and R₁₄ are takentogether with the nitrogen atom to which they are attached to form anoptionally substituted heterocyclic ring; and n is 0, 1, 2, 3 or 4.

Each preferred group stated above can be taken in combination with one,any or all other preferred groups.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graphical representation of the layout of drugs and thecombination of compounds across 96-well plates as described in theExamples.

FIG. 2 is a graphical representation of the percent viral inhibition ofthe compounds or combinations of compounds at every individualconcentration or combination concentration tested as described in theExamples.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment of the present invention is a compound represented byFormula (I) as described above, or a pharmaceutically acceptable salt,ester or prodrug thereof.

The carbon atom at position 3 of the benzodiazepine ring system of thecompounds of the invention is chiral. Thus, compounds of the inventioncan have the stereochemistry depicted in Formula (Ia) or (Ib):

wherein R₁, R₂, R₃, R₄, R₅, R₆, A and n are previously defined. Acomposition of the invention can comprise a compound of the invention asa racemic mixture of Formula Ia and Formula Ib, a pure enantiomer ofeither Formula Ia or Formula Ib, or an excess of one enantiomer over theother. For example, the composition can comprise the compound in anenantiomeric excess of at least 5, 10, 20, 30, 40, 50, 60, 70, 80 or90%. In one embodiment, the enantiomeric excess is at least 95%. Incompounds of the invention having two or more chiral atoms, suchcompounds can be present in a composition as a pure stereoisomer or amixture of stereoisomers, such as a racemic mixture or a mixture ofdiasteromers. In one embodiment, a composition of the inventioncomprises a racemic mixture, a single stereoisomer or enantiomers withan enantiomeric excess of at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90or 95%.

In a preferred embodiment, a compound of the invention is represented byFormula (Ib). Compositions of the invention preferably comprise asubstantially pure compound of Formula (Ib), or a mixture of a compoundof Formula (Ib) and the corresponding compound of Formula (Ia), with anenantiomeric excess of the compound of Formula (Ib) as discussed above.

In certain embodiments, the present invention relates to compounds ofFormula (I), and pharmaceutically acceptable salts thereof, wherein R₁is not hydrogen. In other embodiments, R₁ is hydrogen, optionallysubstituted —C₁-C₈-alkoxy, or optionally substituted CH₃. In certainembodiments, the present invention relates to compounds of Formula (I)and pharmaceutically acceptable salts thereof, wherein R₁ is optionallysubstituted —C₁-C₈-alkoxy, or optionally substituted CH₃, such as, forexample, CF₃.

In certain embodiments, the present invention relates to compounds ofFormula (I), and pharmaceutically acceptable salts thereof, wherein R₂is hydrogen, or optionally substituted CH₃.

In certain embodiments, the present invention relates to compounds ofFormula (I), and pharmaceutically acceptable salts thereof, wherein R₅is hydrogen or optionally substituted CH₃.

In certain embodiments, the present invention relates to compounds ofFormula (I), and pharmaceutically acceptable salts thereof, wherein R₁is hydrogen or optionally substituted CH₃, R₂ is hydrogen and R₅ ishydrogen.

In certain embodiments, the present invention relates to compounds ofFormula (I), and pharmaceutically acceptable salts thereof, wherein R₃is optionally substituted aryl or heteroaryl. Preferably R₃ is phenyland optionally substituted with one to three substituents selected fromthe group consisting of hydrogen, halo, —CF₃, —OCF₃, —CH₃, —SO₂Me, andcyano.

In certain embodiments, the present invention relates to compounds ofFormula (I), and pharmaceutically acceptable salts thereof, wherein A isoptionally substituted aryl, optionally substituted heteroaryl,optionally substituted —C₃-C₈ cycloalkyl or optionally substituted 3- to8-membered heterocyclyl. Preferably A is optionally substituted aryl oroptionally substituted heteroaryl. More preferably A is optionallysubstituted monocyclic 5-membered heteroaryl, a monocyclic 6-memberedheteroaryl or an 8-10-membered fused heteroaryl. In one embodiment, A isa five-membered nitrogen containing heteroaryl group.

In another embodiment, the present invention relates to compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein A isderived from one of the following by removal of two hydrogen atoms:

wherein each of the above shown monocyclic heteroaryl is optionallysubstituted when possible.

In certain embodiments, A is selected from, but not limited to, thegroups set forth below, where one of the indicated valences is the pointof attachment of the heteroaryl group to R₄ and the other is the pointof attachment to the amino nitrogen atom. Each of these groups isoptionally additionally substituted when possible. The atom of A whichconnects A to R₄ can be a carbon atom or, when possible, a nitrogenatom:

Preferably the optional substituents are independently selected fromhalo, —CH₃, —CF₃, —OCF₃, —CN, —SO₂Me, —CH₂N(CH₃)₂, optionallysubstituted —C₁-C₈-alkoxy, and —C(O)CH₃. It is to be understood thatdepending on the heteroaryl group, there can be 0, 1, 2 or 3substituents. In preferred embodiments, there are 0 to 2 substituentsand, more preferably, 0 or 1 substituent.

In another particular embodiment, the present invention relates tocompounds of Formula (I), or a pharmaceutically acceptable salt thereof,wherein A is derived from a fused bicyclic group selected from one ofthe following by removal of two hydrogen atoms.

In this embodiment, A is attached to the amino nitrogen atom and R₄ viaany available ring atoms. In the 5/6 fused rings, A is preferablyattached to the amino nitrogen atom via an available atom in the5-membered ring. In the 6/6 fused rings, A is preferably attached to theamino nitrogen atom via a carbon atom of the nitrogen-containing ring.

In certain embodiments, A is selected from the groups set forth below:

wherein the point of attachment to the amino nitrogen atom is shown andR₄ is attached to any other available ring position and is preferablyhydrogen. In one embodiment, R₄ is attached to an atom of the benzoring. When A is naphthyl, R₄ and the amino nitrogen atom are preferablyattached to carbon atoms from different rings. Each of the above showngroups is optionally substituted, and preferably the optionalsubstituents are independently selected from halo, —CH₃, —CF₃, —OCF₃,—CN, —NH₂, —OH, —CH₂N(CH₃)₂, —C(O)CH₃, —NH—(C₁-C₆)alkyl,—SO₂—(C₁-C₆)alkyl, —SO₂—NH—(C₁-C₆)alkyl, —NH—SO₂—(C₁-C₆)alkyl, and—C₁-C₈-alkoxy. Preferably, in addition to R₄, there are 0, 1, 2 or 3substituents, more preferably 0, 1 or 2 substituents, and morepreferably 0 or 1 substituent.

In certain embodiments of the compounds of the invention, R₄ is nothydrogen. In certain embodiments of the compounds of the invention, R₄is an optionally substituted aryl, optionally substituted heteroaryl,optionally substituted 3- to 12-membered heterocycloalkyl, optionallysubstituted —C₃-C₁₂-cycloalkyl, optionally substituted —C₃-C₁₂cycloalkenyl, optionally substituted aryl-O—, optionally substitutedheteroaryl-O, optionally substituted aryl-C₁-C₄-alkyl or optionallysubstituted heteroaryl-C₁-C₄-alkyl. In certain embodiments, R₄ isphenyl, naphthyl, 5-membered heteroaryl or 6-membered heteroaryl, eachof which is optionally substituted. In certain embodiments, R₄ is anoptionally substituted 5- or 6-membered heteroaryl fused with a6-membered aryl, heteroaryl, carbocyclic or heterocyclic ring, such as abenzo-fused-5- or 6-membered heteroaryl or a pyrido-fused 5- or6-membered heteroaryl.

In certain embodiments of the compounds of the invention, R₄ is a groupderived from one of the following by removal of one hydrogen atom:

wherein each of the above shown is optionally substituted when possible.

In certain embodiments, R₄ is selected from the groups shown below, eachof which is optionally substituted,

In certain embodiments, R₄ is optionally substituted with one or moresubstituents independently selected from halo, —CH₃, —CF₃, —OCF₃, —CN,—NH₂, —OH, —CH₂N(CH₃)₂, —C(O)CH₃, optionally substituted—NH—(C₁-C₆)alkyl, optionally substituted —NH—(C₁-C₆)alkyl-(C₁-C₆)alkoxy,optionally substituted —SO₂—(C₁-C₆)alkyl, optionally substituted—SO₂—NH—(C₁-C₆)alkyl, optionally substituted —NH—SO₂—(C₁-C₆)alkyl,optionally substituted 3- to 12-membered heterocycloalkyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted —C₁-C₈-alkyl, optionally substituted —C₁-C₈-alkenyl,optionally substituted —C₃-C₈-cycloalkyl, optionally substituted—C₃-C₈-cycloalkenyl, and optionally substituted —C₁-C₈-alkoxy. Inanother embodiment, the substituents are independently selected fromCH₃, CN, fluoro, chloro, CH₃O—, CH₃C(O)—, CH₃OCH₂—, CH₃OCH₂CH₂O—, —CF₃,CF₃O—,

In another embodiment, the substituents are independently selected fromCH₃, CN, fluoro, chloro, CH₃O—, CH₃C(O)—, CH₃OCH₂—, CH₃OCH₂CH₂O—, —CF₃,CF₃O—,

In certain embodiments, there are 0 to 4, 0 to 3, 0 to 2, 1 or 0substituents. Preferably, there are 0 to 2 substituents and morepreferably, 0 or 1 substituent. More preferably optionally substitutedgroups can be more than one.

In certain embodiments of the compounds of the invention, A isoptionally substituted aryl, optionally substituted heteroaryl,optionally substituted —C₃-C₈ cycloalkyl or optionally substituted 3- to8-membered heterocyclyl, as described above. In this embodiment, R₄ isan optionally substituted aryl, heteroaryl, 3- to 12-memberedheterocycloalkyl, C₃-C₁₂-cycloalkyl, C₃-C₁₂ cycloalkenyl, aryl-O—,heteroaryl-O, aryl-C₁-C₄-alkyl or heteroaryl-C₁-C₄-alkyl, as describedabove. In this embodiment, R₄ is preferably optionally substituted aryl,heteroaryl, 3- to 12-membered heterocycloalkyl, C₃-C₁₂-cycloalkyl, orC₃-C₁₂ cycloalkenyl. In certain embodiments of the compounds of theinvention, each R₆ is independently halo, optionally substituted methyl,CN or CF₃. In certain embodiments, n is 0 to 3, 0 to 2, 1 or 0. Morepreferably, n is 0.

In certain embodiments of the compounds of the invention, A is amonocyclic 5-membered heteroaryl, optionally substituted with one to twosubstituents independently selected from the group consisting of halo,CF₃, OCF₃, SO₂Me, cyano, optionally substituted —C₁-C₈-alkoxy, andoptionally substituted methyl; R₁ is hydrogen or optionally substitutedmethyl; R₂ is hydrogen; R₃ is optionally substituted aryl; R₄ isoptionally substituted aryl or optionally substituted heteroaryl; R₅ ishydrogen; n is 0. Preferably A is optionally substituted triazole,optionally substituted oxadiazolyl, optionally substituted oxazolyl, oroptionally substituted thiadiazolyl.

In certain embodiments of the compounds of the invention, A is amonocyclic 6-membered heteroaryl optionally independently substitutedwith one to two substituents selected from the group consisting of halo,CF₃, OCF₃, SO₂Me, cyano, optionally substituted —C₁-C₈-alkoxy, andoptionally substituted methyl; R₁ is hydrogen or optionally substitutedmethyl; R₂ is hydrogen; R₃ is optionally substituted aryl; R₄ isoptionally substituted aryl or optionally substituted heteroaryl; R₅ ishydrogen; R₆ is hydrogen. Preferably A is optionally substituted pyridylor optionally substituted pyrimidyl.

In another embodiment of the invention is a compound represented by oneof Formulas (IIa-1), (IIa-2), (IIb-1) and (IIb-2) or a pharmaceuticallyacceptable salt, ester or prodrug thereof:

wherein R₂, R₃, R₄, R₅, R₆, A and n are as previously defined.

In another embodiment of the invention is a compound represented by oneof Formulas (IIIa-1), (IIIa-2), (IIIb-1), and (IIIb-2) or apharmaceutically acceptable salt, ester or prodrug thereof:

wherein R₂, R₃, R₄, R₅, R₆, A and n are as previously defined.

In another embodiment of the invention is a compound represented by oneof Formulas (IV-1)˜(IV-4), (IVa-1)˜(Ia-4), and (IVb-1)˜(IVb-4), or apharmaceutically acceptable salt, ester or prodrug thereof:

wherein, R₁, R₂, R₃, R₄, R₅, R₆ and n are as previously defined.

In another embodiment of the invention is a compound represented by oneof Formulas (V-1)˜(V-3), (Va-1)˜(Va-3), and (Vb-1)˜(Vb-3), or apharmaceutically acceptable salt, ester or prodrug thereof:

wherein, R₁, R₂, R₃, R₄, R₅, R₆ an n are as previously defined.

In another embodiment of the invention is a compound represented by oneof Formulas (VIa-1)˜(VIa-8) and Formulas (VIb-1)˜(VIb-8), or apharmaceutically acceptable salt, ester or prodrug thereof:

wherein R₆ and R₄ are as previously defined, except that R₆ can beabsent, corresponding to n=0 in Formula (I). Preferably R₆ is absent,halo, —CN, —OH, —NH₂, optionally substituted methoxy, or optionallysubstituted methyl; more preferably R₆ is absent. In the compounds ofFormulas (VIa-5) to (VIa-8) and (VIb-5) to (VIb-8), R₄ can be attachedto any available ring atom and is preferably attached to a carbon atomof the benzo ring. In particular embodiments, R₄ for each Formula(VIa-1)˜(VIa-8), (VIb-1)˜(VIb-8) is selected from the groups set forthin Table 1 and can be further optionally substituted (Entry 1 to Entry184 in Table 1).

TABLE 1 Entry R₄ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

It will be appreciated that the description of the present inventionherein should be construed in congruity with the laws and principles ofchemical bonding. In some instances it may be necessary to remove ahydrogen atom in order to accommodate a substituent at any givenlocation.

It is intended that the definition of any substituent or variable (e.g.,R₁, R₂, etc.) at a particular location in a molecule be independent ofits definitions elsewhere in that molecule. For example, in Formula(V-1) when n is 2, each of the two R₆ groups may be the same ordifferent.

It will be yet appreciated that the compounds of the present inventionmay contain one or more asymmetric carbon atoms and may exist inracemic, diastereoisomeric, and optically active forms. It will still beappreciated that certain compounds of the present invention may exist indifferent tautomeric forms. All tautomers are contemplated to be withinthe scope of the present invention.

In certain embodiments, the present invention provides a method for theprevention or treatment of RSV activities and for treating RSV infectionis subjects. The method comprises administering a therapeuticallyeffective amount of a compound of formula (I).

The present invention also provides the use of a compound of formula (I)for the preparation of a medicament for the prevention or treatment ofRSV.

Thus, in one embodiment, a compound of formula (I), or pharmaceuticallyacceptable salt thereof, is combined with a steroid anti-inflammatorycompound, for example budesonide or fluticasone. In a preferredembodiment, the steroid is administered in low doses to minimizeimmuno-suppressant effects. In another embodiment a compound of formula(I), or a pharmaceutically acceptable salt thereof, is combined with anon-steroid anti-inflammatory compound, for example leukotrieneantagonists such as Singulair (Merck) or Accolate (Astra Zeneca),phosphodiesterase 4 inhibitors such as roflumilast (Altana), TNF alphainhibitors such as Enbrel (Amgen), Remicade (Centocor), Humira (Abbott)or CDP870 (Celltech) or NSAIDS. In a further embodiment, a compound offormula (I) is combined with interleukin 8 or interleukin 9 inhibitors.The present invention thus also relates to a product containing acompound of formula (I), or a pharmaceutically acceptable salt thereof,and an anti-inflammatory compound for simultaneous, separate orsequential use in the treatment of RSV.

The present invention also relates to a combination of a compound offormula (I), or a pharmaceutically acceptable salt thereof, with ananti-influenza compound and the use of such a combination in thetreatment of concomitant RSV and influenza infections. The presentinvention thus also relates to a product containing a compound offormula (I), or a pharmaceutically acceptable salt thereof, and ananti-influenza compound for simultaneous, separate or sequential use inthe treatment of concomitant RSV and influenza infections. The compoundsof the invention may be administered in a variety of dosage forms. Thus,they can be administered orally, for example as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules.The compounds of the invention may also be administered parenterally,whether subcutaneously, intravenously, intramuscularly, intrasternally,transdermally or by infusion techniques. The compounds may also beadministered as suppositories.

In certain embodiments, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is administered with one or more additionalagent(s) together in a single pharmaceutical composition. In certainembodiments, a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, is administered with one or more additional agent(s) astwo or more separate pharmaceutical compositions. For example, acompound of Formula (I), or a pharmaceutically acceptable salt thereof,can be administered in one pharmaceutical composition, and at least oneof the additional agents can be administered in a second pharmaceuticalcomposition. If there are at least two additional agents, one or more ofthe additional agents can be in a first pharmaceutical composition thatincludes a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, and at least one of the other additional agent(s) can bein a second pharmaceutical composition.

The order of administration of a compound of Formula (I), or apharmaceutically acceptable salt thereof, with one or more additionalagent(s) can vary. In certain embodiments, a compound of Formula (I), ora pharmaceutically acceptable salt thereof, is administered prior to alladditional agents. In other embodiments, a compound of Formula (I), or apharmaceutically acceptable salt thereof, is administered prior to atleast one additional agent. In still other embodiments, a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, isadministered concomitantly with one or more additional agent(s). In yetstill other embodiments, a compound of Formula (I), or apharmaceutically acceptable salt thereof, is administered subsequent tothe administration of at least one additional agent. In someembodiments, a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, is administered subsequent to the administration of alladditional agents.

After a period of time, infectious agents, such as RSV, can developresistance to one or more therapeutic agents. In certain embodiments, acompound of Formula (I), or a pharmaceutically acceptable salt thereof,is administered to a subject infected with RSV that is resistant to oneor more different anti-RSV agents (for example, ribavirin). In certainembodiments, development of resistant RSV strains is delayed whensubjects are treated with a compound of Formula (I), or apharmaceutically acceptable salt thereof, compared to the development ofRSV strains resistant to other RSV drugs.

In an embodiment, the compounds of the invention are administered byintranasal or intrabronchial administration. The present invention alsoprovides an inhaler or nebuliser containing a medicament which comprises(a) a benzodiazepine derivative of the formula (I), as defined above, ora pharmaceutically acceptable salt thereof, and (b) a pharmaceuticallyacceptable carrier or diluent.

The present invention also provides a pharmaceutical compositioncontaining a compound of Formula I, or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier or diluent. Incertain embodiments, the invention provides pharmaceutical compositionscomprising a compound of Formula I or a pharmaceutically acceptable saltthereof, and at least one additional anti-RSV agent, such as theanti-RSV agents disclosed herein. Preferably, the combinationformulations of the invention comprise a compound of Formula I or apharmaceutically acceptable salt thereof and one or more additionalanti-RSV agent which are bioavailable via the same route ofadministration. In preferred embodiments, the compound of Formula I orpharmaceutically acceptable salt thereof and the additional anti-RSVagent(s) are orally available and the pharmaceutical composition is in aform which is suitable for oral administration.

The compounds and combinations of the invention are typically formulatedfor administration with a pharmaceutically acceptable carrier ordiluent. For example, solid oral forms may contain, together with theactive compound, diluents, e.g. lactose, dextrose, saccharose,cellulose, corn starch or potato starch; lubricants, e.g. silica, talc,stearic acid, magnesium or calcium stearate, and/or polyethyleneglycols; binding agents; e.g. starches, arabic gums, gelatin,methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone;disaggregating agents, e.g. starch, alginic acid, alginates or sodiumstarch glycolate; effervescing mixtures; dyestuffs; sweeteners; wettingagents, such as lecithin, polysorbates, laurylsulphates; and, ingeneral, non toxic and pharmacologically inactive substances used inpharmaceutical formulations. Such pharmaceutical preparations may bemanufactured in known manner, for example, by means of mixing,granulating, tableting, sugar coating, or film coating processes.

Liquid dispersions for oral administration may be syrups, emulsions andsuspensions. The syrups may contain as carriers, for example, saccharoseor saccharose with glycerine and/or mannitol and/or sorbitol.

Suspensions and emulsions may contain as carrier, for example a naturalgum, agar, sodium alginate, pectin, methylcellulose,carboxymethylcellulose, or polyvinyl alcohol. The suspension orsolutions for intramuscular injections may contain, together with theactive compound, a pharmaceutically acceptable carrier, e.g. sterilewater, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and ifdesired, a suitable amount of lidocaine hydrochloride.

Solutions for injection or infusion may contain as carrier, for example,sterile water or preferably they may be in the form of sterile, aqueous,isotonic saline solutions.

The present invention also relates to the novel compounds, as definedabove; or a pharmaceutically acceptable salt thereof, for use in amethod of treating the human or animal body. The present invention alsorelates to a pharmaceutical composition comprising a novel compound asdefined above and a pharmaceutically acceptable diluent or carrier.Preferably, the pharmaceutical composition comprises a pharmaceuticallyacceptable salt of a novel compound as defined above. A pharmaceuticallyacceptable salt is as defined above. The novel compounds of theinvention are typically administered in the manner defined above and thecompounds are typically formulated for administration in the mannerdefined above.

Preferably, the pharmaceutical compositions comprise optically activeisomers of the novel compounds of the invention. Thus, for example,preferred novel compounds of the invention containing only one chiralcentre include an R enantiomer in substantially pure form, an Senantiomer in substantially pure form and enantiomeric mixtures whichcontain an excess of the R enantiomer or an excess of the S enantiomer.It is particularly preferred that pharmaceutical compositions contains acompound of the invention which is a substantially pure optical isomer.For the avoidance of doubt, the novel compounds of the invention can, ifdesired, be used in the form of solvates.

Yet a further aspect of the present invention is a process of making anyof the compounds delineated herein employing any of the synthetic meansdelineated herein.

Definitions

Listed below are definitions of various terms used to describe thisinvention. These definitions apply to the terms as they are usedthroughout this specification and claims, unless otherwise limited inspecific instances, either individually or as part of a larger group.

The term “alkyl”, as used herein, refers to a saturated, monovalentstraight- or branched-chain hydrocarbon radicals. Preferred alkylradicals include C₁-C₆ alkyl and C₁-C₈ alkyl radicals. Examples of C₁-C₆alkyl radicals include, but are not limited to, methyl, ethyl, propyl,isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl radicals; andexamples of C₁-C₈ alkyl groups include, but are not limited to, methyl,ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl,heptyl, and octyl radicals.

The term “alkenyl” as used herein, refers to straight- or branched-chainhydrocarbon radicals having at least one carbon-carbon double bond bythe removal of a single hydrogen atom. Preferred alkenyl groups includeC₂-C₆ alkenyl and C₂-C₈ alkenyl groups. Alkenyl groups include, but arenot limited to, for example, ethenyl, propenyl, butenyl,1-methyl-2-buten-1-yl, heptenyl, octenyl and the like.

The term “alkynyl” as used herein, refers to straight- or branched-chainhydrocarbon radicals having at least one carbon-carbon triple bond bythe removal of a single hydrogen atom. Preferred alkynyl radicalsinclude C₂-C₆ alkynyl and C₂-C₈ alkynyl radicals. Representative alkynylradicals include, but are not limited to, for example, ethynyl,1-propynyl, 1-butynyl, heptynyl, octynyl and the like.

It is understood that any alkyl, alkenyl, alkynyl and cycloalkyl moietydescribed herein can also be an aliphatic group, an alicyclic group or aheterocyclic group. An “aliphatic” group is a non-aromatic moiety thatmay contain any combination of carbon atoms, hydrogen atoms, halogenatoms, oxygen, nitrogen or other atoms, and optionally contain one ormore units of unsaturation, e.g., double and/or triple bonds. Analiphatic group may be straight chained, branched or cyclic andpreferably contains between about 1 and about 24 carbon atoms, moretypically between about 1 and about 12 carbon atoms. In addition toaliphatic hydrocarbon groups, aliphatic groups include, for example,polyalkoxyalkyls, such as polyalkylene glycols, polyamines, andpolyimines, for example. Such aliphatic groups may be furthersubstituted.

The term “alicyclic,” as used herein, denotes a monovalent group derivedfrom a monocyclic or bicyclic saturated carbocyclic ring compound by theremoval of a single hydrogen atom. Examples include, but not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.1]heptyl, and bicyclo [2.2.2] octyl. Such alicyclic groups may be furthersubstituted.

The term “alkynylene” refers to an alkynyl group from which anadditional hydrogen atom has been removed to form a diradical group.Alkynylene groups include, but are not limited to, for example,ethynylene, propynylene, butynylene, 1-methyl-2-butyn-1-ylene,heptynylene, octynylene, and the like.

The term “carbocycle” refers to a saturated (e.g., “cycloalkyl”),partially saturated (e.g., “cycloalkenyl” or “cycloalkynyl”) orcompletely unsaturated (e.g., “aryl”) ring system containing zeroheteroatom ring atom. “Ring atoms” or “ring members” are the atoms boundtogether to form the ring or rings. Where a carbocycle group is adivalent moiety linking two other elements in a depicted chemicalstructure, the carbocycle group can be attached to the two otherelements through any two substitutable ring atoms. A C₄-C₆ carbocyclehas 4-6 ring atoms.

The term “cycloalkyl”, as used herein, refers to a monocyclic orpolycyclic saturated carbocyclic ring compound, and the carbon atoms maybe optionally oxo-substituted. A polycyclic cycloalkenyl can comprisefused rings. Preferred cycloalkyl groups include C₃-C₈ cycloalkyl andC₃-C₁₂ cycloalkyl groups. Examples of C₃-C₈-cycloalkyl include, but arenot limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cyclopentyl and cyclooctyl; and examples of C₃-C₁₂-cycloalkyl include,but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,bicyclo [2.2.1] heptyl, and bicyclo [2.2.2] octyl.

The term “cycloalkenyl”, as used herein, refers to monocyclic orpolycyclic carbocyclic ring compound having at least one carbon-carbondouble bond and the carbon atoms may be optionally oxo-substituted. Apolycyclic cycloalkenyl can comprise fused rings, covalently attachedrings or a combination thereof. Preferred cycloalkenyl groups includeC₃-C₈ cycloalkenyl and C₃-C₁₂ cycloalkenyl groups. Examples ofC₃-C₈-cycloalkenyl include, but are not limited to, cyclopropenyl,cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl,and the like; and examples of C₃-C₁₂-cycloalkenyl include, but notlimited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl,cycloheptenyl, cyclooctenyl, and the like.

The term “heterocycloalkyl” and “heterocyclic” can be usedinterchangeably and refer to a non-aromatic 3-, 4-, 5-, 6-, 7- or 8- or9-12 membered ring or a bi- or tri-cyclic group fused or bridged orspiro system, where: (i) each ring contains between one and threeheteroatoms independently selected from oxygen, sulfur and nitrogen,(ii) each 5-membered ring has 0 to 1 double bonds and each 6-, 7-, 8-,or 9-12 membered ring has 0 to 2 double bonds, (iii) the nitrogen andsulfur heteroatoms may optionally be oxidized, (iv) the nitrogenheteroatom may optionally be quaternized, (v) any of the above rings maybe fused to a benzene ring, and (vi) the remaining ring atoms are carbonatoms which may be optionally oxo-substituted. Representativeheterocycloalkyl groups include, but are not limited to, [1,3]dioxolane,pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl,thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl,2-azabicyclo[2.2.1]heptyl, 8-azabicyclo[3.2.1]octyl,5-azaspiro[2.5]octyl, 1-oxa-7-azaspiro[4.4]nonanyl, and tetrahydrofuryl.Such heterocyclic groups may be further substituted to give substitutedheterocyclic. Heteroaryl or heterocyclic groups can be C-attached orN-attached (where possible).

The term “aryl,” as used herein, refers to a mono- or polycycliccarbocyclic ring system comprising at least one aromatic ring,including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl,indanyl, indenyl and the like. A polycyclic aryl is a polycyclic ringsystem that comprises at least one aromatic ring. Polycyclic aryls cancomprise fused rings, covalently attached rings or a combinationthereof.

The term “heteroaryl,” as used herein, refers to a mono- or polycyclicaromatic radical having one or more ring atom selected from S, O and N;and the remaining ring atoms are carbon, wherein any N or S containedwithin the ring may be optionally oxidized. Preferred heteroaryl groupsare monocyclic or bicyclic. Heteroaryl groups include, but are notlimited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl,imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl,thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl,benzooxazolyl, quinoxalinyl, and the like. A polycyclic heteroaryl cancomprise fused rings, covalently attached rings or a combinationthereof.

In accordance with the invention, aromatic groups can be substituted orunsubstituted.

The term “arylalkyl,” as used herein, refers to functional group whereinan alkylene chain is attached to an aryl group. Examples include, butare not limited to, benzyl, phenethyl and the like. The term“substituted arylalkyl” means an arylalkyl functional group in which thearyl group is substituted. Similarly, the term “heteroarylalkyl” means afunctional group wherein an alkylene chain is attached to a heteroarylgroup. Examples include, but are not limited to, pyridinylmethyl,pyrimidinylethyl and the like. The term “substituted heteroarylalkyl”means a heteroarylalkyl functional group in which the heteroaryl groupis substituted.

The term “alkoxy” employed alone or in combination with other termsmeans, unless otherwise stated, an alkyl group having the designatednumber of carbon atoms connected to the rest of the molecule via anoxygen atom, such as, for example, methoxy, ethoxy, 1-propoxy, 2-propoxy(isopropoxy) and the higher homologs and isomers. Preferred alkoxy are(C₁-C₃) alkoxy.

The term “halo” or halogen” alone or as part of another substituent, asused herein, refers to a fluorine, chlorine, bromine, or iodine atom.

The term “hydrogen” includes hydrogen and deuterium. In addition, therecitation of an atom includes other isotopes of that atom so long asthe resulting compound is pharmaceutically acceptable.

The term “substituted” as used herein, refers to independent replacementof one, two, three or more of the hydrogen atoms thereon withsubstituents including, but not limited to, deuterium, tritium, —F, —Cl,—Br, —I, —OH, protected hydroxy, —NO₂, —CN, —NH₂, —N₃, protected amino,alkoxy, thioalkoxy, oxo, thioxo, —C₁-C₁₂-alkyl, —C₂-C₁₂-alkenyl,—C₂-C₁₂-alkynyl, —C₃-C₁₂-cycloalkyl-halo-C₁-C₁₂-alkyl,-halo-C₂-C₁₂-alkenyl, -halo-C₂-C₁₂-alkynyl, -halo-C₃-C₁₂-cycloalkyl,—NH—C₁-C₁₂-alkyl, —NH—C₂-C₁₂-alkenyl, —NH—C₂-C₁₂-alkynyl,—NH—C₃-C₁₂-cycloalkyl, —NH-aryl, —NH-heteroaryl, —NH-heterocycloalkyl,-dialkylamino, -diarylamino, -diheteroarylamino, —O—C₁-C₁₂-alkyl,—O—C₂-C₁₂-alkenyl, —O—C₂-C₁₂-alkynyl, —O—C₃-C₁₂-cycloalkyl, —O-aryl,—O-heteroaryl, —O-heterocycloalkyl, —C(O)—C₁-C₁₂-alkyl,—C(O)—C₂-C₁₂-alkenyl, —C(O)—C₂-C₁₂-alkynyl, —C(O)—C₃-C₁₂-cycloalkyl,—C(O)-aryl, —C(O)-heteroaryl, —C(O)-heterocycloalkyl, —CONH₂,—CONH—C₁-C₁₂-alkyl, —CONH—C₂-C₁₂-alkenyl, —CONH—C₂-C₁₂-alkynyl,—CONH—C₃-C₁₂-cycloalkyl, —CONH-aryl, —CONH-heteroaryl,—CONH-heterocycloalkyl, —OCO₂—C₁-C₁₂-alkyl, —OCO₂—C₂-C₁₂-alkenyl,—OCO₂—C₂-C₁₂-alkynyl, —OCO₂—C₃-C₁₂-cycloalkyl, —OCO₂-aryl,—OCO₂-heteroaryl, —OCO₂-heterocycloalkyl, —OCONH₂, —OCONH—C₁-C₁₂-alkyl,—OCONH—C₂-C₁₂-alkenyl, —OCONH—C₂-C₁₂-alkynyl, —OCONH—C₃-C₁₂-cycloalkyl,—OCONH-aryl, —OCONH— heteroaryl, —OCONH-heterocycloalkyl,—NHC(O)—C₁-C₁₂-alkyl, —NHC(O)—C₂-C₁₂-alkenyl, —NHC(O)—C₂-C₁₂-alkynyl,—NHC(O)—C₃-C₁₂-cycloalkyl, —NHC(O)-aryl, —NHC(O)-heteroaryl,—NHC(O)-heterocycloalkyl, —NHCO₂—C₁-C₁₂-alkyl, —NHCO₂—C₂-C₁₂-alkenyl,—NHCO₂—C₂-C₁₂-alkynyl, —NHCO₂—C₃-C₁₂-cycloalkyl, —NHCO₂-aryl,—NHCO₂-heteroaryl, —NHCO₂-heterocycloalkyl, —NHC(O)NH₂,—NHC(O)NH—C₁-C₁₂-alkyl, —NHC(O)NH—C₂-C₁₂-alkenyl,—NHC(O)NH—C₂-C₁₂-alkynyl, —NHC(O)NH—C₃-C₁₂-cycloalkyl, —NHC(O)NH-aryl,—NHC(O)NH— heteroaryl, —NHC(O)NH-heterocycloalkyl, NHC(S)NH₂,—NHC(S)NH—C₁-C₁₂-alkyl, —NHC(S)NH—C₂-C₁₂-alkenyl,—NHC(S)NH—C₂-C₁₂-alkynyl, —NHC(S)NH—C₃-C₁₂-cycloalkyl, —NHC(S)NH-aryl,—NHC(S)NH-heteroaryl, —NHC(S)NH-heterocycloalkyl, —NHC(NH)NH₂,—NHC(NH)NH—C₁-C₁₂-alkyl, —NHC(NH)NH—C₂-C₁₂-alkenyl,—NHC(NH)NH—C₂-C₁₂-alkynyl, —NHC(NH)NH—C₃-C₁₂-cycloalkyl,—NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl, —NHC(NH)NH-heterocycloalkyl,—NHC(NH)—C₁-C₁₂-alkyl, —NHC(NH)—C₂-C₁₂-alkenyl, —NHC(NH)—C₂-C₁₂-alkynyl,—NHC(NH)—C₃-C₁₂-cycloalkyl, —NHC(NH)-aryl, —NHC(NH)— heteroaryl,—NHC(NH)-heterocycloalkyl, —C(NH)NH—C₁-C₁₂-alkyl,—C(NH)NH—C₂-C₁₂-alkenyl, —C(NH)NH—C₂-C₁₂-alkynyl,—C(NH)NH—C₃-C₁₂-cycloalkyl, —C(NH)NH-aryl, —C(NH)NH— heteroaryl,—C(NH)NH-heterocycloalkyl, —S(O)—C₁-C₁₂-alkyl, —S(O)—C₂-C₁₂-alkenyl,—S(O)—C₂-C₁₂-alkynyl, —S(O)—C₃-C₁₂-cycloalkyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)-heterocycloalkyl —SO₂NH₂, —SO₂NH—C₁-C₁₂-alkyl,—SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₂-C₁₂-alkynyl, —SO₂NH—C₃-C₁₂-cycloalkyl,—SO₂NH-aryl, —SO₂NH-heteroaryl, —SO₂NH-heterocycloalkyl,—NHSO₂—C₁-C₁₂-alkyl, —NHSO₂—C₂-C₁₂-alkenyl, —NHSO₂—C₂-C₁₂-alkynyl,—NHSO₂—C₃-C₁₂-cycloalkyl, —NHSO₂-aryl, —NHSO₂-heteroaryl,—NHSO₂-heterocycloalkyl, —CH₂NH₂, —CH₂SO₂CH₃, -aryl, -arylalkyl,-heteroaryl, -heteroarylalkyl, -heterocycloalkyl, —C₃-C₁₂-cycloalkyl,polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, —SH,—S—C₁-C₁₂-alkyl, —S—C₂-C₁₂-alkenyl, —S—C₂-C₁₂-alkynyl,—S—C₃-C₁₂-cycloalkyl, —S-aryl, —S-heteroaryl, —S-heterocycloalkyl,methylthiomethyl, or -L′-R′, wherein L′ is C₁-C₆alkylene,C₂-C₆alkenylene or C₂-C₆alkynylene, and R′ is aryl, heteroaryl,heterocyclic, C₃-C₁₂cycloalkyl or C₃-C₁₂cycloalkenyl. It is understoodthat the aryls, heteroaryls, alkyls, and the like can be furthersubstituted. In some cases, each substituent in a substituted moiety isadditionally optionally substituted with one or more groups, each groupbeing independently selected from C₁-C₆-alkyl, —F, —Cl, —Br, —I, —OH,—NO₂, —CN, or —NH₂.

The term “optionally substituted”, as used herein, means that thereferenced group may be substituted or unsubstituted. In one embodiment,the referenced group is optionally substituted with zero substituents,i.e., the referenced group is unsubstituted. In another embodiment, thereferenced group is optionally substituted with one or more additionalgroup(s) individually and independently selected from groups describedherein.

In accordance with the invention, any of the aryls, substituted aryls,heteroaryls and substituted heteroaryls described herein, can be anyaromatic group. Aromatic groups can be substituted or unsubstituted.

It is understood that any alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclic and cycloalkenyl moiety described herein can also be analiphatic group or an alicyclic group.

An “aliphatic” group is a non-aromatic moiety comprised of anycombination of carbon atoms, hydrogen atoms, halogen atoms, oxygen,nitrogen or other atoms, and optionally contains one or more units ofunsaturation, e.g., double and/or triple bonds. Examples of aliphaticgroups are functional groups, such as alkyl, alkenyl, alkynyl, O, OH,NH, NH₂, C(O), S(O)₂, C(O)O, C(O)NH, OC(O)O, OC(O)NH, OC(O)NH₂, S(O)₂NH,S(O)₂NH₂, NHC(O)NH₂, NHC(O)C(O)NH, NHS(O)₂NH, NHS(O)₂NH₂, C(O)NHS(O)₂,C(O)NHS(O)₂NH or C(O)NHS(O)₂NH₂, and the like, groups comprising one ormore functional groups, non-aromatic hydrocarbons (optionallysubstituted), and groups wherein one or more carbons of a non-aromatichydrocarbon (optionally substituted) is replaced by a functional group.Carbon atoms of an aliphatic group can be optionally oxo-substituted. Analiphatic group may be straight chained, branched, cyclic, or acombination thereof and preferably contains between about 1 and about 24carbon atoms, more typically between about 1 and about 12 carbon atoms.In addition to aliphatic hydrocarbon groups, as used herein, aliphaticgroups expressly include, for example, alkoxyalkyls, polyalkoxyalkyls,such as polyalkylene glycols, polyamines, and polyimines, for example.Aliphatic groups may be optionally substituted.

The term “alicyclic,” as used herein, denotes a monovalent group derivedfrom a monocyclic or polycyclic saturated carbocyclic ring compound bythe removal of a single hydrogen atom. Examples include, but are notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1] heptyl, and bicyclo [2.2.2] octyl. Such alicyclic groups may befurther substituted.

It is understood that any alkyl, alkenyl, alkynyl, alicyclic,cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, aliphaticmoiety or the like, described herein can also be a divalent ormultivalent group when used as a linkage to connect two or more groupsor substituents, which can be at the same or different atom(s). One ofskill in the art can readily determine the valence of any such groupfrom the context in which it occurs.

The term “hydroxy activating group”, as used herein, refers to a labilechemical moiety which is known in the art to activate a hydroxy group sothat it will depart during synthetic procedures such as in asubstitution or elimination reactions. Examples of hydroxy activatinggroup include, but are not limited to, mesylate, tosylate, triflate,p-nitrobenzoate, phosphonate and the like.

The term “activated hydroxy”, as used herein, refers to a hydroxy groupactivated with a hydroxy activating group, as defined above, includingmesylate, tosylate, triflate, p-nitrobenzoate, phosphonate groups, forexample.

The term “protected hydroxy,” as used herein, refers to a hydroxy groupprotected with a hydroxy protecting group, as defined above, includingbenzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups,for example.

The term “hydroxy protecting group,” as used herein, refers to a labilechemical moiety which is known in the art to protect a hydroxy groupagainst undesired reactions during synthetic procedures. After saidsynthetic procedure(s) the hydroxy protecting group as described hereinmay be selectively removed. Hydroxy protecting groups as known in theart are described generally in T. H. Greene and P. G., S. M. Wuts,Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons,New York (1999). Examples of hydroxy protecting groups includebenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl,4-methoxybenzyloxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl,isopropoxycarbonyl, diphenylmethoxycarbonyl,2,2,2-trichloroethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl,2-furfuryloxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl,trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t-butyl,2,2,2-trichloroethyl, 2-trimethylsilyl ethyl, 1,1-dimethyl-2-propenyl,3-methyl-3-butenyl, allyl, benzyl, para-methoxybenzyldiphenylmethyl,triphenylmethyl (trityl), tetrahydrofuryl, methoxymethyl,methylthiomethyl, benzyloxymethyl, 2,2,2-triehloroethoxymethyl,2-(trimethyl silyl)ethoxymethyl, methanesulfonyl, para-toluenesulfonyl,trimethylsilyl, triethylsilyl, triisopropylsilyl, and the like.Preferred hydroxy protecting groups for the present invention are acetyl(Ac or —C(O)CH₃), benzoyl (Bz or —C(O)C₆H₅), and trimethylsilyl (TMS or—Si(CH₃)₃), and the like.

The term “hydroxy prodrug group,” as used herein, refers to a promoietygroup which is known in the art to change the physicochemical, and hencethe biological properties of a parent drug in a transient manner bycovering or masking the hydroxy group. After said syntheticprocedure(s), the hydroxy prodrug group as described herein must becapable of reverting back to hydroxy group in vivo. Hydroxy prodruggroups as known in the art are described generally in Kenneth B. Sloan,Prodrugs, Topical and Ocular Drug Delivery, (Drugs and thePharmaceutical Sciences; Volume 53), Marcel Dekker, Inc., New York(1992).

The term “amino protecting group,” as used herein, refers to a labilechemical moiety which is known in the art to protect an amino groupagainst undesired reactions during synthetic procedures. After saidsynthetic procedure(s) the amino protecting group as described hereinmay be selectively removed. Amino protecting groups as known in the artare described generally in T. H. Greene and P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York(1999). Examples of amino protecting groups include, but are not limitedto, methoxycarbonyl, t-butoxycarbonyl, 9-fluorenyl-methoxycarbonyl,benzyloxycarbonyl, and the like.

The term “protected amino,” as used herein, refers to an amino groupprotected with an amino protecting group as defined above.

The term “leaving group” means a functional group or atom which can bedisplaced by another functional group or atom in a substitutionreaction, such as a nucleophilic substitution reaction. By way ofexample, representative leaving groups include chloro, bromo and iodogroups; sulfonic ester groups, such as mesylate, tosylate, brosylate,nosylate and the like; and acyloxy groups, such as acetoxy,trifluoroacetoxy and the like.

The compounds described herein contain one or more asymmetric centersand thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)- or (S)-, or as (D)- or (L)- for amino acids.The present invention is meant to include all such possible isomers, aswell as their racemic and optically pure forms. Optical isomers may beprepared from their respective optically active precursors by theprocedures described above, or by resolving the racemic mixtures. Theresolution can be carried out in the presence of a resolving agent, bychromatography or by repeated crystallization or by some combination ofthese techniques, which are known to those skilled in the art. Furtherdetails regarding resolutions can be found in Jacques, et al.,Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981). Whenthe compounds described herein contain olefinic double bonds or othercenters of geometric asymmetry, and unless specified otherwise, it isintended that the compounds include both E and Z geometric isomers.Likewise, all tautomeric forms are also intended to be included. Theconfiguration of any carbon-carbon double bond appearing herein isselected for convenience only and is not intended to designate aparticular configuration unless the text so states; thus a carbon-carbondouble bond depicted arbitrarily herein as trans may be cis, trans, or amixture of the two in any proportion.

Certain compounds of the present invention may also exist in differentstable conformational forms which may be separable. Torsional asymmetrydue to restricted rotation about an asymmetric single bond, for examplebecause of steric hindrance or ring strain, may permit separation ofdifferent conformers. The present invention includes each conformationalisomer of these compounds and mixtures thereof.

The term “subject” as used herein refers to a mammal. A subjecttherefore refers to, for example, dogs, cats, horses, cows, pigs, guineapigs, and the like. Preferably the subject is a human. When the subjectis a human, the subject may be referred to herein as a patient.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts of the compounds formed by the process of the presentinvention which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art.

Berge, et al. describes pharmaceutically acceptable salts in detail inJ. Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be preparedin situ during the final isolation and purification of the compounds ofthe invention, or separately by reacting the free base function with asuitable organic acid. Examples of pharmaceutically acceptable saltsinclude, but are not limited to, nontoxic acid addition salts e.g.,salts of an amino group formed with inorganic acids such as hydrochloricacid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloricacid or with organic acids such as acetic acid, maleic acid, tartaricacid, citric acid, succinic acid or malonic acid or by using othermethods used in the art such as ion exchange. Other pharmaceuticallyacceptable salts include, but are not limited to, adipate, alginate,ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate,butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like. Representative alkali or alkaline earth metal saltsinclude sodium, lithium, potassium, calcium, magnesium, and the like.Further pharmaceutically acceptable salts include, when appropriate,nontoxic ammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and arylsulfonate.

Pharmaceutically acceptable salts can also be prepared by deprotonationof the parent compound with a suitable base, thereby forming the anionicconjugate base of the parent compound. In such salts the counter ion isa cation. Suitable cations include ammonium and metal cations, such asalkali metal cations, including Li⁺, Na⁺, K⁺ and Cs⁺, and alkaline earthmetal cations, such as Mg²⁺ and Ca²⁺.

As used herein, the term “pharmaceutically acceptable ester” refers toesters of the compounds formed by the process of the present inventionwhich hydrolyze in vivo and include those that break down readily in thehuman body to leave the parent compound or a salt thereof. Suitableester groups include, for example, those derived from pharmaceuticallyacceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic,cycloalkanoic and alkanedioic acids, in which each alkyl or alkenylmoiety advantageously has not more than 6 carbon atoms. Examples ofparticular esters include, but are not limited to, formates, acetates,propionates, butyrates, acrylates and ethylsuccinates.

The term “pharmaceutically acceptable prodrugs” as used herein refers tothose prodrugs of the compounds formed by the process of the presentinvention which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswith undue toxicity, irritation, allergic response, and the like,commensurate with a reasonable benefit/risk ratio, and effective fortheir intended use, as well as the zwitterionic forms, where possible,of the compounds of the present invention. “Prodrug”, as used hereinmeans a compound, which is convertible in vivo by metabolic means (e.g.by hydrolysis) to afford any compound delineated by the formulae of theinstant invention. Various forms of prodrugs are known in the art, forexample, as discussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier(1985); Widder, et al. (ed.), Methods in Enzymology, Vol. 4, AcademicPress (1985); Krogsgaard-Larsen, et al., (ed.). “Design and Applicationof Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191(1991); Bundgaard, et al., Journal of Drug Deliver Reviews, 8:1-38(1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq. (1988);Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems,American Chemical Society (1975); and Bernard Testa & Joachim Mayer,“Hydrolysis In Drug And Prodrug Metabolism: Chemistry, Biochemistry AndEnzymology,” John Wiley and Sons, Ltd. (2002).

Additional types of prodrugs are also encompassed. For instance, freecarboxyl groups can be derivatized as amides or alkyl esters. Freehydroxy groups may be derivatized using groups including but not limitedto hemisuccinates, ethyl succinate, phosphate esters,dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, as outlinedin Advanced Drug Delivery Reviews, 1996, 19, 115. Carbamate prodrugs ofhydroxy and amino groups are also included, as are carbonate prodrugs,sulfonate esters and sulfate esters of hydroxy groups. Derivatization ofhydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers wherein theacyl group may be an alkyl ester, optionally substituted with groupsincluding but not limited to ether, amine and carboxylic acidfunctionalities, or where the acyl group is an amino acid ester asdescribed above, are also encompassed. Prodrugs of this type aredescribed in J. Med. Chem. 1996, 39, 10. Free amines can also bederivatized as amides, sulfonamides or phosphonamides. All of theseprodrug moieties may incorporate groups including but not limited toether, amine and carboxylic acid functionalities. In certainembodiments, a compound of the invention can incorporate two or moregroups that are metabolically removed in vivo to yield the active parentcompound. For example, a compound of formula I wherein R₁ is an aminoacid residue can also be esterified, for example at a hydroxyl group ofthe sugar residue, to form a compound with two groups that can beremoved in vivo to yield the active compound.

The term “treating”, as used herein, means relieving, lessening,reducing, eliminating, modulating, or ameliorating, i.e. causingregression of the disease state or condition. Treating can also includeinhibiting, i.e. arresting the development, of a existing disease stateor condition, and relieving or ameliorating, i.e. causing regression ofan existing disease state or condition, for example when the diseasestate or condition may already be present.

The term “preventing”, as used herein means, to completely or almostcompletely stop a disease state or condition, from occurring in apatient or subject, especially when the patient or subject ispredisposed to such or at risk of contracting a disease state orcondition.

The terms “therapeutically effective amount” and “effective amount” areused to indicate an amount of an active compound, or pharmaceuticalagent, that elicits the biological or medicinal response indicated. Inthe case of a combination therapy, i.e., the administration of two ormore active pharmaceutical agents, a therapeutically effective amount isan amount of each agent which in combination elicits the desiredresponse, even if the amount of any one agent in the combination is notsufficient, in itself, to provide such a response. For example, atherapeutically effective amount of a compound or a combination ofcompounds is the amount of said compound or combination of compoundsneeded to prevent, treat, alleviate or ameliorate one or more symptomsor conditions of disease or prolong the survival of the subject beingtreated. This response may occur in a tissue, system, animal or humanand includes alleviation of the signs or symptoms of the disease beingtreated. Determination of an effective amount of a compound or acombination of two or more compounds is well within the capability ofthose skilled in the art, in view of the disclosure provided herein. Thetherapeutically effective amount of the compounds disclosed hereinrequired as a dose will depend on the route of administration, the typeof animal, including human, being treated, and the physicalcharacteristics of the specific animal under consideration. The dose canbe tailored to achieve a desired effect, but will depend on such factorsas weight, diet, concurrent medication and other factors which thoseskilled in the medical arts will recognize.

Various indicators for determining the effectiveness of a method fortreating a viral infection, such as a paramyxovirus, are known to thoseskilled in the art. Example of suitable indicators include, but are notlimited to, a reduction in viral load, a reduction in viral replication,a reduction in viral RNA, a reduction in time to seroconversion (virusundetectable in patient serum), a reduction of morbidity or mortality inclinical outcomes, and/or other indicator of disease response.

In some embodiments, an effective amount of a compound of Formula (I),or a pharmaceutically acceptable salt thereof, is an amount that iseffective to reduce viral titers to essentially undetectable or very lowlevels, for example, to less than 1.7 Log 10 plaque forming unitsequivalents (PFUe)/mL, or less than 0.3 Log 10 plaque forming unitsequivalents (PFUe)/mL. In some embodiments, a compound of Formula (I),or a pharmaceutically acceptable salt thereof, can reduce the viral loadcompared to the viral load before administration of the combination (forexample, 60 hours after receiving the initial dosage of thecombination). In some embodiments, a compound of Formula (I), or apharmaceutically acceptable salt thereof, described herein can reducethe viral load to lower than 1.7 Log 10 (PFUe)/mL, or lower than 0.3 Log10 (PFUe)/mL. In some embodiments, a combination of compounds describedherein can achieve a reduction in viral titer in the serum of thesubject in the range of about 1.5-log to about a 2.5-log reduction,about a 3-log to about a 4-log reduction, or a greater than about 5-logreduction compared to the viral load before administration of thecombination. For example, the viral load is measured beforeadministration of the combination, and several hours after receiving theinitial dosage of the combination (for example, 60 hours after receivingthe initial dosage of the combination).

The term “resistant” as used herein refers to a viral strain displayinga delayed, lessened and/or null response to a therapeutic agent(s). Forexample, after treatment with an antiviral agent, the viral load of asubject infected with a resistant virus may be reduced to a lesserdegree compared to the amount in viral load reduction exhibited by asubject infected with a nonresistant strain.

Additionally, the compounds of the present invention, including thesalts of the compounds, can exist in either hydrated or unhydrated (theanhydrous) form or as solvates with other solvent molecules. Nonlimitingexamples of hydrates include monohydrates, dihydrates, etc. Nonlimitingexamples of solvates include ethanol solvates, acetone solvates, etc.

“Solvates” means solvent addition forms that contain eitherstoichiometric or non stoichiometric amounts of solvent. Some compoundshave a tendency to trap a fixed molar ratio of solvent molecules in thecrystalline solid state, thus forming a solvate. If the solvent is waterthe solvate formed is a hydrate, when the solvent is alcohol, thesolvate formed is an alcoholate. Hydrates are formed by the combinationof one or more molecules of water with one of the substances in whichthe water retains its molecular state as H₂O, such combination beingable to form one or more hydrate.

As used herein, the term “analog” refers to a chemical compound that isstructurally similar to another but differs slightly in composition (asin the replacement of one atom by an atom of a different element or inthe presence of a particular functional group, or the replacement of onefunctional group by another functional group). Thus, an analog is acompound that is similar to or comparable in function and appearance tothe reference compound.

The term “aprotic solvent,” as used herein, refers to a solvent that isrelatively inert to proton activity, i.e., not acting as a proton-donor.Examples include, but are not limited to, hydrocarbons, such as hexaneand toluene, for example, halogenated hydrocarbons, such as, forexample, methylene chloride, ethylene chloride, chloroform, and thelike, heterocyclic compounds, such as, for example, tetrahydrofuran andN-methylpyrrolidinone, and ethers such as diethyl ether,bis-methoxymethyl ether. Such solvents are well known to those skilledin the art, and individual solvents or mixtures thereof may be preferredfor specific compounds and reaction conditions, depending upon suchfactors as the solubility of reagents, reactivity of reagents andpreferred temperature ranges, for example. Further discussions ofaprotic solvents may be found in organic chemistry textbooks or inspecialized monographs, for example: Organic Solvents PhysicalProperties and Methods of Purification, 4th ed., edited by John A.Riddick et al., Vol. II, in the Techniques of Chemistry Series, JohnWiley & Sons, N Y, 1986.

The terms “protogenic organic solvent” or “protic solvent” as usedherein, refer to a solvent that tends to provide protons, such as analcohol, for example, methanol, ethanol, propanol, isopropanol, butanol,t-butanol, and the like. Such solvents are well known to those skilledin the art, and individual solvents or mixtures thereof may be preferredfor specific compounds and reaction conditions, depending upon suchfactors as the solubility of reagents, reactivity of reagents andpreferred temperature ranges, for example. Further discussions ofprotogenic solvents may be found in organic chemistry textbooks or inspecialized monographs, for example: Organic Solvents PhysicalProperties and Methods of Purification, 4th ed., edited by John A.Riddick et al., Vol. II, in the Techniques of Chemistry Series, JohnWiley & Sons, N Y, 1986.

Combinations of substituents and variables envisioned by this inventionare only those that result in the formation of stable compounds. Theterm “stable”, as used herein, refers to compounds which possessstability sufficient to allow manufacture and which maintains theintegrity of the compound for a sufficient period of time to be usefulfor the purposes detailed herein (e.g., therapeutic or prophylacticadministration to a subject).

The synthesized compounds can be separated from a reaction mixture andfurther purified by a method such as column chromatography, highpressure liquid chromatography, or recrystallization. Additionally, thevarious synthetic steps may be performed in an alternate sequence ororder to give the desired compounds. In addition, the solvents,temperatures, reaction durations, etc. delineated herein are forpurposes of illustration only and variation of the reaction conditionscan produce the desired bridged macrocyclic products of the presentinvention. Synthetic chemistry transformations and protecting groupmethodologies (protection and deprotection) useful in synthesizing thecompounds described herein include, for example, those described in R.Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2d.Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser andFieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); andL. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, JohnWiley and Sons (1995).

The compounds of this invention may be modified by appending variousfunctionalities via synthetic means delineated herein to enhanceselective biological properties. Such modifications include those whichincrease biological penetration into a given biological system (e.g.,blood, lymphatic system, central nervous system), increase oralavailability, increase solubility to allow administration by injection,alter metabolism and alter rate of excretion.

Pharmaceutical Compositions

The pharmaceutical compositions of the present invention comprise atherapeutically effective amount of a compound of Formula I or apharmaceutically acceptable salt thereof or a therapeutically effectiveamount of a combination of a compound of Formula I or a pharmaceuticallyacceptable salt thereof and at least one additional anti-RSV agentformulated together with one or more pharmaceutically acceptablecarriers. As used herein, the term “pharmaceutically acceptable carrier”means a non-toxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type. Someexamples of materials which can serve as pharmaceutically acceptablecarriers are sugars such as lactose, glucose and sucrose; starches suchas corn starch and potato starch; cellulose and its derivatives such assodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; excipients such as cocoabutter and suppository waxes; oils such as peanut oil, cottonseed oil;safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols;such a propylene glycol; esters such as ethyl oleate and ethyl laurate;agar; buffering agents such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol, and phosphate buffer solutions, as well asother non-toxic compatible lubricants such as sodium lauryl sulfate andmagnesium stearate, as well as coloring agents, releasing agents,coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator. The pharmaceuticalcompositions of this invention can be administered to humans and otheranimals orally, rectally, parenterally, intracisternally,intravaginally, intraperitoneally, topically (as by powders, ointments,or drops), buccally, or as an oral or nasal spray.

The pharmaceutical compositions of this invention may be administeredorally, parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir, preferably by oraladministration or administration by injection. The pharmaceuticalcompositions of this invention may contain any conventional non-toxicpharmaceutically-acceptable carriers, adjuvants or vehicles. In somecases, the pH of the formulation may be adjusted with pharmaceuticallyacceptable acids, bases or buffers to enhance the stability of theformulated compound or its delivery form. The term parenteral as usedherein includes subcutaneous, intracutaneous, intravenous,intramuscular, intraarticular, intraarterial, intrasynovial,intrasternal, intrathecal, intralesional and intracranial injection orinfusion techniques.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsmay contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1, 3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolution,which, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle. Injectable depot forms are made by forming microencapsulematrices of the drug in biodegradable polymers such aspolylactide-polyglycolide. Depending upon the ratio of drug to polymerand the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions which are compatible with body tissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or: a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositionswhich can be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, eye ointments, powders and solutionsare also contemplated as being within the scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants suchas chlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlleddelivery of a compound to the body. Such dosage forms can be made bydissolving or dispensing the compound in the proper medium. Absorptionenhancers can also be used to increase the flux of the compound acrossthe skin. The rate can be controlled by either providing a ratecontrolling membrane or by dispersing the compound in a polymer matrixor gel.

As will be readily apparent to one skilled in the art, the useful invivo dosage to be administered and the particular mode of administrationwill vary depending upon the age, weight, the severity of theaffliction, and mammalian species treated, the particular compoundsemployed, and the specific use for which these compounds are employed.The determination of effective dosage levels, that is the dosage levelsnecessary to achieve the desired result, can be accomplished by oneskilled in the art using routine methods, for example, human clinicaltrials and in vitro studies.

Unless otherwise defined, all technical and scientific terms used hereinare accorded the meaning commonly known to one with ordinary skill inthe art. All publications, patents, published patent applications, andother references mentioned herein are hereby incorporated by referencein their entirety.

Combination and Alternation Therapy for RSV

In certain aspects, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition that includes acompound described herein, is used in combination with one or moreadditional agent(s). In certain embodiments, a compound of Formula (I),or a pharmaceutically acceptable salt thereof, is used in combinationwith one or more agents currently used in a conventional standard ofcare for treating RSV. For example, the additional agent can beribavirin, palivizumab, and RSV-IGIV. For the treatment of RSV,additional anti-RSV agents include but are not limited to an anti-RSVantibody, a fusion protein inhibitor, an N-protein inhibitor, a RSVpolymerase inhibitor, an IMPDH inhibitor, an interferon and an othercompound that inhibits the RSV virus, or a pharmaceutically acceptablesalt of any of the foregoing. A non-limiting list of examples ofadditional agents is provided herein.

Pharmaceutical Drug name Drug category Company IUPAC Name or StructureGS-5806 Fusion inhibitor GileadN-(2-((5)-2-(5-((S)-3-aminopyrrolidin-1-yl)-6-methylpyrazolo[1,5-a]pyrimidin-2-yl)piperidine-1-carbonyl)-4-chlorophenyl)methanesulfonamide

BTA9881 Fusion inhibitor Aviragen(R)-9b-(4-chlorophenyl)-1-(4-fluorobenzoyl)-2,3-dihydro-1H-imidazo[1′,2′:1,2]pyrrolo[3,4-c]pyridin-5(9bH)-one

BMS-433771 Fusion inhibitor Bristol-Myers1-cyclopropyl-3-U1-(4-hydroxybutyl)benzimidazol-2- Squibbyl]methyl]imidazo[4,5-c]pyridin-2-one

JNJ-2408068 Fusion inhibitor Janssen2-[[2-[[1-(2-aminoethyl)-4-piperidinyl]amino]-4-methyl-1H-benzimidazol-1-yl]-6-methyl-3-pyridinol

TMC-353121 Fusion inhibitor Janssen 2-[[6-[[[2-(3-Hydroxypropyl)-5-ethylphenyl]amino]methyl]-2-[[3-(morpholin-4-yl)propyl]amino]benzimidazol-1-yl]methyl]-6- methylpyridin-3-ol

JNJ-53718678 Fusion inhibitor Janssen

VP-14637 Fusion inhibitor MicroDose5,5′-bis[1-(((5-amino-1H-tetrazolyl)imino)methyl)]2,2′,4″- (MDT-637)methylidynetrisphenol

AK0529 Fusion inhibitor Ark Biosciences RV521 Fusion inhibitor ReviralMIV-323 Fusion inhibitor Medivir RFI-641 Fusion inhibitor4,4″-bis-{4,6-bis-[3-(bis-carbamoylmethyl-sulfamoyl)-phenylamino]-(1,3,5)triazin-2-ylamino]-biphenyl-2,2″- disulfonic-acid

R═N(CH₂CONH₂)₂ CL387626 Fusion inhibitor4,4-Bis[4,6-di[3-aminophenyl-N,N-bis(2-carbamoylethyl)-sulfonilimino]-1,3,5-triazine-2-ylamino]-biphenyl-2,2′- disulfonic acid,disodium salt R170591 Fusion inhibitor2-((2-((1-(2-aminoethyl)piperidin-4-yl)amino)-4-methyl-1H-benzo[d]imidazol-1-yl)methyl)-6-methylpyridin-3-ol

P13 Fusion inhibitor N-(2-hydroxyethyl)-4-methoxy-N-methyl-3-(6-methyl-[1,2,4]triazolo[3,4-a]phtalazin-3-yl)bensenesulfonamide

C15 Fusion inhibitor 1,4-bis(3-methylpyridin-4-yl)-1,4-diazepane

MBX-300 Fusion inhibitor[2,2-bis(docosyloxy-oxymethyl)propyl-5-acetaoamido-3,5-dideoxy-4,7,8,9-tetra-0-(sodium-oxysulfonyl)-D-glycero-D-galacto-2-nonulopyranosid]onate

BTA585 Fusion inhibitor Aviragen (Biota) T-67 peptide fusion peptidehaving the sequence inhibitor DEFDASISQVNEKINQSLAFERKSDELL T118 peptidefusion a peptide having the sequence inhibitorFDASISQVNEKINQSLAFERKSDELLHNVNAGKST YM-53403 L polymerase Yamanouchi6-{4-[(biphenyl-2-ylcarbonyl)amino]benzoyll-N-cyclopropyl- inhibitor5,6-dihydro-4H-thieno[3,2-d][1]benzazepine-2-carboxamide

AZ-27 L polymerase Astra Zeneca 6-(4-(2-(2-oxa-7-azaspiro[3.5]nonan-7-inhibitor yl)nicotinamido)benzoyl)-N-cyclopropyl-5,6-dihydro-4H-benzo[b]thieno[2,3-d]azepine-2- carboxamide

PC786 L polymerase inhibitor Pulmocide

JNJ-64417184 L polymerase Janssen inhibitor L polymeraseN-cyclopropyl-5-(4-(2-(pyrrolidin-1-yl)benzamido)benzoyl)- inhibitor5,6,7,10- tetrahydrobenzo[b]cyclopentaazepine-9-carboxamide

L polymerase 6-(4-(2-(2-oxa-7-azaspiro[3.5]nonan-7- inhibitoryl)nicotinamido)benzoyl)-N-cyclopropyl-5,6-dihydro-4H-benzo[b]thieno[2,3-d]azepine-2- carboxamide L polymerase4-amino-8-(3-ft2-(3,4- inhibitordimethoxyphenyl)ethyflaminolpropyl)-6,6-dimethyl-2-(4-methyl-3-nitrophenyl)-1H-imidazo[4,5-N- isoquinoline-7,9(6H,8H)-dione (CAS Reg. No. 851658-10-1) L polymerase(2R,3R,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)- inhibitoryl)-2-(chloromethyl)-4-fluoro-2-(hydroxymethyl)tetrahydrofuran-3-ylisobutyrate

L polymerase ((2R,3R,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)- inhibitoryl)-2-(chloromethyl)-4-fluoro-3- hydroxytetrahydrofuran-2-yl)methyltriphosphate

motavizumab Anti-RSV MedImmune, (MEDI-524) antibodies targeting AstraZeneca Fusion protein Palivizumab Anti-RSV MedImmune (Synagis ®)antibodies RSV-IGIV Anti-RSV MedImmune (RespiGam ®) antibodies MEDI-8897Anti-RSV antibodies targeting Fusion protein REGN2222 Anti-RSVantibodies targeting Fusion protein ALX-0171 Anti-RSV Ablynx antibodiestargeting Fusion protein: anti-RSV nanobody MK-1654 Anti-RSV Merckantibodies targeting Fusion protein ribavirin1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-1H-1,2,4-triazole-3- carboxamide

EICAR IMPDH inhibitor 5-ethynyl-1-beta-D-ribofuranosylimidazole-4-carboxamide

pyrazofurin IMPDH inhibitor 4-hydroxy-3-beta-D-ribofuranosylpyrazole-5-carboxamide

Taribavirin IMPDH inhibitor 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(viramidine) (hydroxymethyl)tetrahydrofuran-2-yl)-1H-1,2,4-triazole-3-carboximidamide

LY253963 IMPDH inhibitor 1,3,4-thiadiazol-2-ylcyanamide

VX-497 IMPDH inhibitor Vertextetrahydrofuran-3-yl-3-(3-(3-methoxy-4-(oxazol-5-yl)phenyl)ureido)benzylcarbamate

Mycophenolic IMPDH inhibitor(4E)-6-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3- aciddihydro-2-benzofuran-5-yl)-4-methylhex-4-enoic acid

Mycophenolate IMPDH inhibitor2-morpholin-4-ylethyl-(E)-6-(4-hydroxy-6-methoxy-7-methyl- Mofetil3-oxo-1H-2-benzofuran-5-yl)-4-methylhex-4-enoate

Type 1 interferon Interferon Type 2 interferon Interferon Type 3interferon Interferon IFN-a Interferon IFN-β Interferon IFN-λ InterferonPEGASYS ® Interferon Pegylated interferon-alpha-2a PEG-INTRON ®Interferon Pegylated interferon-alpha-2b INFERGEN ® Interferoninterferon alfacon-1 ALS-8112 Nucleoside Alios BioPharma4-amino-1-((2R,3R,4R,5R)-5-(chloromethyl)-3-fluoro-4- inhibitorhydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin- 2(1H)-one

ALS-8176 Nucleoside Alios BioPharma(2R,3R,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2- inhibitor(chloromethyl)-4-fluoro-2- ((isobutylyloxy)methyl)tetrahydrofuran-3-ylisobutyrate

RSV-604 N-protein inhibitors(S)-1-(2-fluorophenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)urea

iKT-041 N-protein inhibitors Inhibikase SRI 29365 G protein inhibitorChemBridge mAb 131-2G a non-neutralizing mAb against the G proteinALN-RSV01 siRNA targeting Alnylam an siRNA agent with the sense strandsequence (5′ to 3′) RSV Pharmaceuticals GGCUCUUAGCAAAGUCAAGdTdT (SEQ IDNO. 3), and the antisense strand sequence (5′ to 3′)CUUGACUUUGCUAAGAGCCdTdT (SEQ ID NO. 4) ALN-RSV02 Alnylam PharmaceuticalsSTP-92 siRNA delivered Sirnaomics through nanoparticle based deliverysystems Medi-559 Medi-557 Medi-534 leflumomide5-methyl-N-[4-(trifluoromethyl)phenyl]-isoxazole-4- carboxamide

JMN3-003 N-(2-chloro-4-methylphenyl)-2-((1-(4-methoxyphenyl)-1H-benzo[d]imidazol-2-yl)thio)propanamide

RI-001 ADMA high titer, human immunoglobulin Biologics Inc. CG-100 anintratracheal formulation of recombinant human CC10 CAS No. 851685- CASNo. 851685-10-1 10-1 4-amino-8-(3-{[2-(3,4-dimethoxyphenyl)ethyl]amino}propyl)-6,6-dimethyl-2-(4-methyl-3-nitrophenyl)-1H-imidazo[4,5-hFisoquinoline- 7,9(6H,8H)-dione.

Other examples of compounds that can be used in combination with acompound of Formula (I), or a pharmaceutically acceptable salt thereof,include those provided in WO 2013/186333, published Dec. 19, 2013; WO2013/186332, published Dec. 19, 2013; WO 2013/186335, published Dec. 19,2013; WO 2013/186334, published Dec. 19, 2013; WO 2012/080447, publishedJun. 21, 2012; WO 2012/080449, published Jun. 21, 2012; WO 2012/080450,published Jun. 21, 2012; WO 2012/080451, published Jun. 21, 2012; WO2012/080446, published Jun. 21, 2012; WO 2010/103306, published Sep. 16,2010; WO 2012/068622, published May 31, 2012; WO 2005/042530, publishedMay 12, 2005; WO 2006/136561, published Dec. 28, 2006; WO 2005/058869,published Jun. 30, 2005; U.S. 2013/0090328, published Apr. 11, 2013; WO2014/009302, published Jan. 16, 2014; WO 2011/005842, published Jan. 13,2011; U.S. 2013/0273037, published Oct. 17, 2013; U.S. 2013/0164280,published Jun. 27, 2013; U.S. 2014/0072554, published Mar. 13, 2014; WO2014/031784, published Feb. 27, 2014 and WO 2015/026792, published Feb.26, 2015, all of which are hereby incorporated by reference.

In combination therapy, the additional agents can be administered inamounts that have been shown to be effective for those additionalagents. Such amounts are known in the art; alternatively, they can bederived from viral load or replication studies using the parameters for“effective amount” set forth above. Alternatively, the amount used canbe less than the effective monotherapy amount for such additionalagents. For example, the amount used could be between 90% and 5% of suchamount, e.g., 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, or 5%, orintermediate values between those points.

A potential advantage of utilizing a compound of Formula (I), or apharmaceutically acceptable salt thereof, in combination with one ormore additional agent(s) including pharmaceutically acceptable salts andprodrugs thereof, may be a reduction in the required amount(s) of one ormore compounds described above (including those set forth in the table)including pharmaceutically acceptable salts and prodrugs thereof that iseffective in treating a disease condition disclosed herein (for example,RSV), as compared to the amount required to achieve same therapeuticresult when one or more compounds described above (including those setforth in the table), including pharmaceutically acceptable saltsthereof, are administered without a compound of Formula (I), or apharmaceutically acceptable salt thereof. For example, the amount of acompound described above, including a pharmaceutically acceptable saltand prodrug thereof, can be less compared to the amount of the compoundabove, including a pharmaceutically acceptable salt and prodrug thereof,needed to achieve the same viral load reduction when administered as amonotherapy.

Another potential advantage of utilizing a compound of Formula (I), or apharmaceutically acceptable salt thereof, in combination with one ormore additional agent(s) described above (including the table),including pharmaceutically acceptable salts and prodrugs thereof, isthat the use of two or more compounds having different mechanisms ofaction can create a higher barrier to the development of resistant viralstrains compared to the barrier when a compound is administered asmonotherapy.

Additional advantages of utilizing a compound of Formula (I), or apharmaceutically acceptable salt thereof, in combination with one ormore additional agent(s) described above (including the table),including pharmaceutically acceptable salts and prodrugs thereof, mayinclude little to no cross resistance between a compound of Formula (I),or a pharmaceutically acceptable salt thereof, and one or moreadditional agent(s) described above, including pharmaceuticallyacceptable salts and prodrugs thereof; different routes for eliminationof a compound of Formula (I), or a pharmaceutically acceptable saltthereof, and one or more additional agent(s) described above, includingpharmaceutically acceptable salts and prodrugs thereof; little to nooverlapping toxicities between a compound of Formula (I), or apharmaceutically acceptable salt thereof, and one or more additionalagent(s) described above, including pharmaceutically acceptable saltsand prodrugs thereof; little to no significant effects on cytochromeP450; and/or little to no pharmacokinetic interactions between acompound of Formula (I), or a pharmaceutically acceptable salt thereof,and one or more additional agent(s) described above, includingpharmaceutically acceptable salts and prodrugs thereof).

It will be understood that the administration of the combination of theinvention can be by means of a single patient pack, or patient packs ofeach formulation, containing within a package insert instructing thepatient to the correct use of the invention is a desirable additionalfeature of this invention.

Unless otherwise defined, all technical and scientific terms used hereinare accorded the meaning commonly known to one of ordinary skill in theart. All publications, patents, published patent applications, and otherreferences mentioned herein are hereby incorporated by reference intheir entirety.

Abbreviations

Abbreviations which have been used in the descriptions of the schemesand the examples that follow are:

ACN for acetonitrile;BAST for bis(2-methoxyethyl)aminosulfur trifluoride;BME for 2-mercaptoethanol;BOP for benzotriazol-1-yloxy-tris(dimethylamino)phosphoniumhexafluorophosphate;BTC for bis(trichloromethyl)carbonate; triphosgene;BzCl for benzoyl chloride;CDI for carbonyldiimidazole;COD for cyclooctadiene;DABCO for 1,4-diazabicyclo[2.2.2]octane;DAST for diethylaminosulfur trifluoride;DABCYL for 6-(N-4′-carboxy-4-(dimethylamino)azobenzene)-aminohexyl-;1-O-(2-cyanoethyl)-(N,N-diisopropyl)-phosphoramidite;

DBU for 1, 8-Diazabicycloundec-7-ene;

DCC for N, N′-dicyclohexylcarbodiimide;DCM for dichloromethane;DIAD for diisopropyl azodicarboxylate;DIBAL-H for diisobutylaluminum hydride;DIPEA for diisopropyl ethylamine;

DMAP for N,N-dimethylaminopyridine;

DMA for N,N-dimethyl acetamide;DME for ethylene glycol dimethyl ether;

DMEM for Dulbecco's Modified Eagles Media;

DMF for N,N-dimethyl formamide;DMSO for dimethylsulfoxide;DSC for N, N′-disuccinimidyl carbonate;

DUPHOS for

EDANS for 5-(2-Amino-ethylamino)-naphthalene-1-sulfonic acid;EDCI or EDC for 1-(3-diethylaminopropyl)-3-ethylcarbodiimidehydrochloride;EtOAc or EA for ethyl acetate;EtOH for ethyl alcohol;HATU for O (7-Azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate;HCl for hydrochloric acid;Hoveyda's Cat. for Dichloro(o-isopropoxyphenylmethylene)(tricyclohexylphosphine)ruthenium(II);In for indium;KHMDS is potassium bis(trimethylsilyl) amide;Ms for mesyl;NMM for N-4-methylmorpholine;

NMI for N-methylimidazole;

NMO for N-4-methylmorpholine-N-Oxide;PyBrOP for Bromo-tri-pyrolidino-phosphonium hexafluorophosphate;PE for petroleum ether;Ph for phenyl;RCM for ring-closing metathesis;RT for reverse transcription;RT-PCR for reverse transcription-polymerase chain reaction;TBME for tert-butyl methyl ether;TCDI for 1,1′-thiocarbonyldiimidazole;TEA for triethyl amine;Tf₂O for trifluoromethanesulfonic anhydride;TFA for trifluoroacetic acid;THF for tetrahydrofuran;TLC for thin layer chromatography;(TMS)₂NH for hexamethyldisilazane;TMSOTf for trimethylsilyl trifluoromethanesulfonate;TBS for t-Butyldimethylsilyl;TMS for trimethylsilyl;TPAP tetrapropylammonium perruthenate;TPP or PPh₃ for triphenylphosphine;TrCl for trityl chloride;DMTrCl for 4,4′-dimethoxytrityl chloride;tBOC or Boc for tert-butyloxy carbonyl;Xantphos for 4,5-Bis-diphenylphosphanyl-9,9-dimethyl-9H-xanthene; and

Zhan 1 B for

Synthetic Methods

The compounds and processes of the present invention will be betterunderstood in connection with the following synthetic schemes thatillustrate the methods by which the compounds of the invention may beprepared, which are intended as an illustration only and not to limitthe scope of the invention. Various changes and modifications to thedisclosed embodiments will be apparent to those skilled in the art andsuch changes and modifications including, without limitation, thoserelating to the chemical structures, substituents, derivatives, and/ormethods of the invention may be made without departing from the spiritof the invention and the scope of the appended claims.

As shown in Scheme 1, novel RSV analogs of the compounds of formula 10or 11 are prepared starting from compounds 1, 2, and 3. A proceduresimilar to that described by Sherrill and Sugg (J. Org. Chem. 1995, 60,730-734) was followed to get to the intermediate having the formula 8.Firstly, 1, 2, and 3 are heated in an appropriate solvent like, but notlimited to, toluene to form compound 4. Compound 4 is converted to thecorresponding acid chloride, using the appropriate conditions, and isthen reacted with 5, wherein n, R₃, R₅, and R₆ are as previouslydefined, to form compound 6. Compound 6 is reacted with ammonia,followed by reaction with ammonium acetate in acetic acid to formcompound 7. The Cbz group in 7 is removed using HBr in acetic acid toafford the intermediate amine 8. Compound 8 is a common intermediatethat will be used in various ways to access compounds of the formula (10or 11). Following Path 1, 8 is reacted with 9 via a displacement of thehalogen (X) or via suitable coupling conditions using Pd or Cu catalyststo afford compounds of formula 10, wherein A and R₄ are defined aspreviously described. Compounds 10 can be reacted further via alkylationwith reagents like, but not limited to, alkyl halides, mesylates andtosylates or via reductive amination with aldehydes and ketones toinstall R₂, wherein R₂ is defined as previously described, to givecompounds of formula 11. Following Path 2 reverses the reaction sequenceby alkylating 8 with reagents like, but not limited to, alkyl halides,mesylates and tosylates or via reductive amination with aldehydes andketones to install R₂, wherein R₂ is defined as previously described,giving 12 which is reacted further with 9, via displacement or Pd/Cucatalyzed reactions, to give compounds of formula 11.

Scheme 2 illustrates alternative methods, wherein n, R₂, R₃, R₄, R₅, R₆,and A are defined as previously described, to prepare compounds offormula (11). Following Path 1, compound 12 is reacted with thedi-halide 13, where X is a halogen that may or may not be the same, viadisplacement of one halogen (X) or via suitable coupling conditionsusing Pd or Cu catalysts to afford compounds of formula 14. Compound 14is reacted further with appropriate coupling partners selected from, butnot limited to, boronic acids, boronic esters, organotin reagents,organozinc reagents, organomagnesium reagents, organo silicon reagents,amines, and alcohols, in combination with the appropriate Pd, Ni, or Cucatalyst to afford compounds of formula 11. The aforementioned reactioncan also be run in an atmosphere of carbon monoxide to affordcorresponding ketones, amides, and esters of formula 11. Compound 14 canalso reacted with an appropriate amine, alcohol, or thiol to form 11 viaa displacement reaction. Following path 2, 12 is reacted with halide 15via a displacement of the halogen (X) or via suitable couplingconditions using Pd or Cu catalysts to afford compounds of formula 16.Compound 16 is reacted further with appropriate coupling partnersselected from, but not limited to, boronic acids, boronic esters,organotin reagents, and organozinc reagents in combination with copper(I) thiophenecarboxylate (CuTC) and the appropriate Pd, Ni, or Cucatalyst to afford compounds of formula 11. Alternatively, compound 16can be oxidized to the corresponding sulfoxide or sulfone using anappropriate oxidant like, but not limited to, m-CPBA, H₂O₂, or Oxone,followed by displacement with an appropriate amine, alcohol, or thiol toform 11.

Scheme 3 illustrates methods, wherein n, R₂, R₃, R₄, R₅, and R₆ aredefined as previously described, to prepare compounds of formulas 20,21, 22 and 23. Following Path 1 amine 8 is reacted with1,1′-thiocarbonyldiimidazole (TCDI) to generate the intermediate 17 thatis reacted directly with hydrazides to afford compounds of formula 18.Compounds of formula 18 can be reacted with1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) to give theoxadiazoles of formula 20. Compound 20 can be reacted further viaalkylation or reductive amination to install R₂, wherein R₂ is definedas previously described, to give compounds of formula 21. Compounds offormula 18 can also be reacted with tosyl chloride (TsCl) to afford thethiadiazoles of formula 22 that can be reacted further via alkylationwith reagents like, but not limited to, alkyl halides, mesylates andtosylates or via reductive amination with aldehydes and ketones toinstall R₂, wherein R₂ is defined as previously described, to givecompounds of formula 23. Following Path 2 the intermediate 17 is reacteddirectly with hydrazine to form compound 19. Compound 19 is then coupledto a carboxylic acid using an appropriate coupling reagent such as, butnot limited to, EDCI with HOBt or HATU to afford compound 18 which isconverted to the compounds 20, 21, 22, and 23 as described above.

Scheme 4 illustrates methods, wherein n, R₂, R₃, R₄, R₅, and R₆ aredefined as previously described, to prepare compounds of formula 20 and(21). Compounds 8 or (can be reacted with oxadiazolones is the presenceof a coupling reagent such as, but not limited to,(Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate(BOP) to afford compounds of formula 20 and can be reacted further viaalkylation with reagents like, but not limited to, alkyl halides,mesylates and tosylates or via reductive amination with aldehydes andketones to install R₂, wherein R₂ is defined as previously described, togive compounds of formula 21. Alternatively compounds 12 can be reactedwith oxadiazolones is the presence of (BOP) to afford compounds offormula 21.

Scheme 5 illustrates methods, wherein n, R₂, R₃, R₄, R₅, and R₆ aredefined as previously described, to prepare compounds of formula 23, 24,26, and, 27. Following Path 1, amine 8 is reacted with TCDI to generatethe intermediate 17 that is reacted with alpha-azido ketones to generatethe oxazole 23. Compound 23 can be reacted further via alkylation withreagents like, but not limited to, alkyl halides, mesylates andtosylates or via reductive amination with aldehydes and ketones toinstall R₂, wherein R₂ is defined as previously described, to givecompounds of formula 24. Following Path 2, 8 is reacted with TCDI togenerate the intermediate thiourea 25 which is reacted further withalpha-bromo ketones to form the thiazoles having a formula like 26, thatcan react further via alkylation with reagents like, but not limited to,alkyl halides, mesylates and tosylates or via reductive amination withaldehydes and ketones to install R₂, wherein R₂ is defined as previouslydescribed, to give compounds of formula 27.

Scheme 6 illustrates methods, wherein n, R₂, R₃, R₄, R₅, and R₆ aredefined as previously described, to prepare compounds of formula 29, 30,32, and 33. Following Path 1, amine 8 is reacted with isothiocyanates togive the intermediate (28) that is reacted further with hydrazine togive triazoles having the formula 29. Compound 29 can be reacted furthervia alkylation with reagents like, but not limited to, alkyl halides,mesylates and tosylates or via reductive amination with aldehydes andketones to install R₂, wherein R₂ is defined as previously described, togive compounds of formula 30. Following Path 2, (8) is reacted with TCDIfollowed by alpha-amino ketones to give the thioureas 31. Reaction of 31with sulfuric acid affords the thiazoles having the formula 32 that canbe reacted further via alkylation with reagents like, but not limitedto, alkyl halides, mesylates and tosylates or via reductive aminationwith aldehydes and ketones to install R₂, wherein R₂ is defined aspreviously described, to give compounds of formula 33.

Scheme 7 illustrates methods, wherein n, R₂, R₃, R₄, R₅, and R₆ aredefined as previously described, to prepare compounds of formulas 20 and21. Amine 8 is reacted with BTC to give the intermediate isocyanate 34that is reacted further with hydrazides to give intermediates 35.Reaction of 35 with PPh₃ and CCl₄ affords the oxadiazoles 20 that canthen be reacted further via alkylation with reagents like, but notlimited to, alkyl halides, mesylates and tosylates or via reductiveamination with aldehydes and ketones to install R₂, wherein R₂ isdefined as previously described, to give compounds of formula 33.

Scheme 8 illustrates methods, wherein n, R₂, R₃, R₄, R₅, and R₆ aredefined as previously described, to prepare compounds of formula 37 and38. Amine 8 is reacted with isothiocyanates to give the intermediate 28that is reacted further with methyl iodide to give intermediates 36.Reaction of 36 with hydroxyl amine-HCl salt affords the1,2,4-oxadiazoles 37 that can then be reacted further via alkylationwith reagents like, but not limited to, alkyl halides, mesylates andtosylates or via reductive amination with aldehydes and ketones toinstall R₂, wherein R₂ is defined as previously described, to givecompounds of formula 38.

Scheme 9 illustrates methods, wherein n, R₁, R₂, R₃, R₄, R₅, and R₆ aredefined as previously described, to prepare compounds of formula 43. Thecompound 39 is reacted under basic conditions with alkyl halides to givecompound 40. Compound 40 is reacted again under basic conditions withelectrophilic azide sources (like trisyl azide) to afford theintermediate azide 41. Reduction of 41 with PPh₃, or some other suitablereductant, gives the amine 42 that can be reacted similarly to thatdescribed in schemes 1-8 to afford the target compounds 43.

Scheme 10 illustrates methods, wherein n, R₁, R₂, R₃, R₄, R₅, and R₆ aredefined as previously described, to prepare compounds of formula 43. Theamine 8 is condensed with an aryl aldehyde give the corresponding imine44. The imine 44 is reacted under basic conditions with alkyl halides togive compound 45. Hydrolysis of the imine 45 under acidic conditionsaffords the amine 42 that can be reacted similarly to that described inschemes 1-8 to afford the target compounds 43.

Scheme 11 illustrates methods, wherein n, R₃, R₄, R₅, and R₆ are definedas previously described, to prepare compounds of formula 48. The racemicamine 8 is converted to the enantiomerically pure amine 44 by twodifferent paths 1 and 2. Following path 1 uses the method described bySherrill and Sugg (J. Org. Chem. 1995, 60, 730-734) to access the chiralamine 44. Alternatively, chiral amine 44 can be accessed by SFCseparation of the racemic amine 8. Amine 44 is reacted with CDI toafford intermediate 45 that is reacted further with the hydrazides 46 togive the corresponding amino semicarbazides 47. The amino semicarbazides47 can be cyclized to the corresponding oxadiazoles 48 using TsCl,POCl₃, and related activating agents.

EXAMPLES

The compounds and processes of the present invention will be betterunderstood in connection with the following examples, which are intendedas an illustration only and not limiting of the scope of the invention.Various changes and modifications to the disclosed embodiments will beapparent to those skilled in the art and such changes and modificationsincluding, without limitation, those relating to the chemicalstructures, substituents, derivatives, formulations and/or methods ofthe invention may be made without departing from the spirit of theinvention and the scope of the appended claims. Unless otherwiseindicated, each of the compounds of the examples below was prepared andtested as a racemic mixture or, when possible, a diastereomeric mixture.

Example 1

Example 1 Step a

To a 250 mL flask equipped mechanical stirring, was added 2-oxoaceticacid hydrate (9.2 g, 0.1 mol), benzyl carbamate (15.1 g, 0.1 mol) and1H-benzo[d][1,2,3]triazole (9.2 g, 0.1 mol), and toluene (300 mL). Theresulting solution was stirred for 2 h at 120° C. in an oil bath. Theresulting mixture was filtered and the solid residue was washed withpetroleum ether (3×), and dried in vacuo to give2-(1H-benzo[d][1,2,3]triazol-1-yl)-2-(benzyloxycarbonylamino)acetic acid(28.6 g, 87%) as a white solid that was used without furtherpurification. ESI-MS m/z: 327 [M+H]⁺.

Example 1 Step b

To a 500-mL 3-necked round-bottom flask, was added2-(1H-1,2,3-benzotriazol-1-yl)-2-[[(benzyloxy)carbonyl]amino]acetic acid(46.3 g, 91.94 mmol) and tetrahydrofuran (200 mL). The reaction mixturewas cooled to 0° C. and a solution of oxalyl chloride (17.6 g, 1.00equiv) in tetrahydrofuran (40 mL) was added dropwise, followed by theaddition of DMF (8 mL). The resulting solution was stirred for 2 h at 0°C. then treated with a THF solution (160 mL) of N-methylmorpholine (28.6g, 280.7 mmol) and 2-benzoylaniline (22.3 g, 80.0 mmol) in portions at0° C. The cold bath was removed and the resulting solution stirred for30 min at room temperature. The solids were filtered off and thefiltrate was evaporated to dryness to afford benzylN-[[(2-benzoylphenyl)carbamoyl](1H-1,2,3-benzotriazol-1-yl)methyl]carbamate(40.4 g, 87%) as a yellow oil that was used without furtherpurification. ESI-MS m/z: 504 [M−H]⁻.

Example 1 Step c

To a 250-mL round-bottom flask, was added benzylN-[[(2-benzoylphenyl)carbamoyl](1H-1,2,3-benzotriazol-1-yl)methyl]carbamate(40.4. g, 80.00 mmol), methanol (200 mL), and ammonia (200 mL). Thereaction mixture was stirred for 3 h at room temperature, concentratedin vacuo, and the residue was diluted with EtOAc (200 mL). The resultingsolution was washed with 1M sodium hydroxide (2×100 mL), dried overanhydrous sodium sulfate, and filtered. The filtrate was concentrated invacuo to give benzylN-[amino[(2-benzoylphenyl)carbamoyl]methyl]carbamate (30.2 g, 93%) asyellow oil that was used without further purification. To a 500-mLround-bottom flask, was added benzylN-[amino[(2-benzoylphenyl)carbamoyl]methyl]carbamate (30.2 g, 74.8mmol), acetic acid (200 mL), and CH₃COONH₄ (28.00 g, 363.3 mmol). Thereaction mixture was stirred for 16 h at room temperature, concentratedin vacuo, and the residue was diluted with EtOAc:ether=1:3 (100 mL). ThepH value of the solution was adjusted to 8 with 1M sodium hydroxide andthe precipitate was collected by filtration to afford of (Z)-benzyl2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-ylcarbamate (14.5g, 50%) as a pink solid that was used without further purification.ESI-MS m/z: 386 [M+H]⁺.

Example 1 Step d

Into a 50 mL round-bottom flask, was placed (Z)-benzyl2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-ylcarbamate (300mg, 0.60 mmol), HBr/HOAc (20 mL). The resulting solution was stirred for30 min at 70° C. in an oil bath. The resulting solution was diluted with20 mL of ether. The solids were collected by filtration to give 270 mg(crude) of (Z)-3-amino-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-onehydrobromide as a yellow solid that was used without furtherpurification. ESI-MS m/z: 252 [M+H]⁺.

Example 1 Step e

The crude (Z)-3-amino-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-onehydrobromide from step d (38.7 g) was dissolved in 50 mL water, thenNH₃.H₂O was added slowly in ice-water bath to adjust the PH to 14. Thesolid was filtered and washed with a small amount of water. The solidwas collected and dried under vacuum to afford(Z)-3-amino-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one (16.8 g) asyellow solid and used without further purification. ESI-MS m/z: 252[M+H]⁺.

Example 1 Step f

A solution of methyl 3-hydroxybenzoate (4 g, 26.3 mmol), 2-bromoethylmethyl ether (7.3 g, 52.6 mmol) and K₂CO₃ in acetone (50 mL) wasrefluxed for 16 hours, the mixture was cooled to room temperature andfiltered. The filtrate was concentrated, dissolved in DCM, and washedwith saturated aqueous NaHCO₃ (×2). The organic layer was dried(Na₂SO₄), concentrated, and purified by column chromatography (silica,petroleum ether: EtOAc) to give desired compound as light yellow oil(3.3 g, 59.6%). ESI-MS m/z: 252.2 [M+MeCN+H]⁺.

Example 1 Step g

A solution of the compound from step f (3.3 g, 15.7 mmol) in EtOH (20mL) and NH₂NH₂. H₂O (2 mL) was refluxed for 48 hours. The mixture wasconcentrated, diluted with ether (100 mL), and the resulting precipitatewas collected by filtration to give the desired compound (2.6 g, 79%) asa white solid, which was used directly in the next step without furtherpurification. ESI-MS m/z: 211.1 [M+H]⁺.

Example 1 Step h

Triphosgene (3.7 g, 12.4 mmol) in THF (10 mL) was added dropwise to thesolution of the compound from step g (1.3 g, 6.2 mmol) and Et₃N (1.7 mL,12.4 mmol) in THF (30 mL) at 0° C. and it was heated to reflux for 16hours. The reaction was quenched with water and concentrated, and theresulting residue was dissolved in EtOAc. The organic layer was washedwith water, dried (Na₂SO₄), and concentrated to give5-(3-(2-methoxyethoxy)phenyl)-1,3,4-oxadiazol-2(3H)-one as a yellowsolid (600 mg, 41%) that was used without further purification. ESI-MSm/z: 237.2 [M+H]⁺.

Example 1 Step i

A solution of the compound from step h (350 mg, 1.48 mmol), BOP (654 mg,1.48 mmol), (Z)-3-amino-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one (149mg, 0.59 mmol) and DIPEA (305 mg, 2.37 mmol) in DMF (3 mL) was stirredfor 36 hours at room temperature. Then the reaction mixture was purifiedby prep-HPLC to give the title compound as a white solid (10 mg, 4%).ESI-MS m/z: 470.3 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 3.33 (s, 3H), 3.68(m, 2H), 4.11-4.21 (m, 2H), 5.16 (d, J=8.6 Hz, 1H), 7.13 (d, J=8.0 Hz,1H), 7.22-7.57 (m, 9H), 7.61-7.71 (m, 1H), 9.12 (d, J=8.4 Hz, 1H), 11.00(s, 1H).

Example 2

Example 2 was prepared using a procedure similar to that used to prepareExample 1 where 5-phenyl-1,3,4-oxadiazol-2(3H)-one was used in place of5-(3-(2-methoxyethoxy)phenyl)-1,3,4-oxadiazol-2(3H)-one. ESI-MS m/z:396.1 [M+H]⁺.

Example 3

Example 3 was prepared using a procedure similar to that used to prepareExample 1 where 5-(3-fluorophenyl)-1,3,4-oxadiazol-2(3H)-one was used inplace of 5-(3-(2-methoxyethoxy)phenyl)-1,3,4-oxadiazol-2(3H)-one. ESI-MSm/z: 414.1 [M+H]⁺.

Example 4

Example 4 was prepared using a procedure similar to that used to prepareExample 1 where 5-(3-methoxyphenyl)-1,3,4-oxadiazol-2(3H)-one was usedin place of 5-(3-(2-methoxyethoxy)phenyl)-1,3,4-oxadiazol-2(3H)-one.ESI-MS m/z: 426.2 [M+H]⁺.

Example 5 was prepared using a procedure similar to that used to prepareExample 1 where 5-cyclopropyl-1,3,4-oxadiazol-2(3H)-one was used inplace of 5-(3-(2-methoxyethoxy)phenyl)-1,3,4-oxadiazol-2(3H)-one. ESI-MSm z: 360.1 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 0.78-0.93 (m, 2H), 1.02(dt, J=8.3, 3.2 Hz, 2H), 2.05 (tt, J=8.4, 5.0 Hz, 1H), 5.04 (d, J=8.7Hz, 1H), 7.20-7.38 (m, 3H), 7.39-7.61 (m, 5H), 7.67 (ddd, J=8.4, 7.0,1.8 Hz, 1H), 8.67 (d, J=8.7 Hz, 1H), 10.93 (s, 1H).

Example 6

Example 6 was prepared using a procedure similar to that used to prepareExample 1 where 5-(2-fluorophenyl)-1,3,4-oxadiazol-2(3H)-one was used inplace of 5-(3-(2-methoxyethoxy)phenyl)-1,3,4-oxadiazol-2(3H)-one. ESI-MSm/z: 414.1 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 5.19 (d, J=8.4 Hz, 1H),7.25-7.55 (m, 10H), 7.58-7.72 (m, 2H), 7.87 (m, 1H), 9.23 (d, J=8.5 Hz,1H), 11.00 (s, 1H).

Example 7

Example 7 was prepared using a procedure similar to that used to prepareExample 1 where 5-(4-fluorophenyl)-1,3,4-oxadiazol-2(3H)-one was used inplace of 5-(3-(2-methoxyethoxy)phenyl)-1,3,4-oxadiazol-2(3H)-one. ESI-MSm/z: 414.1 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 5.17 (dd, J=8.2, 5.2 Hz,1H), 7.23-7.60 (m, 10H), 7.69 (ddd, J=8.5, 7.0, 1.7 Hz, 1H), 7.89 (ddd,J=7.0, 5.4, 2.8 Hz, 2H), 9.17 (d, J=8.5 Hz, 1H), 10.89 (s, 1H).

Example 7a

Example 7a was separated from racemic Example 7 using a reverse phasechiral column (Gemini-NX C18 110A). ESI-MS m/z: 414.2 [M+H]⁺.

Example 7b

Example 7b was separated from racemic Example 7 using a reverse phasechiral column (Gemini-NX C18 110A). ESI-MS m/z: 414.2 [M+H]⁺.

Example 8

Example 8 was prepared using a procedure similar to that used to prepareExample 1 where 5-(4-methoxyphenyl)-1,3,4-oxadiazol-2(3H)-one was usedin place of 5-(3-(2-methoxyethoxy)phenyl)-1,3,4-oxadiazol-2(3H)-one.ESI-MS m/z: 426.3 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 5.16 (d, J=8.4 Hz,1H), 7.09-7.19 (m, 2H), 7.24-7.42 (m, 3H), 7.43-7.60 (m, 5H), 7.69 (ddd,J=8.6, 7.1, 1.8 Hz, 1H), 7.75-7.85 (m, 2H), 9.02 (d, J=8.6 Hz, 1H),10.99 (s, 1H).

Example 9

Example 9 was prepared using a procedure similar to that used to prepareExample 1 where 5-(2-methoxyphenyl)-1,3,4-oxadiazol-2(3H)-one was usedin place of 5-(3-(2-methoxyethoxy)phenyl)-1,3,4-oxadiazol-2(3H)-one.ESI-MS m/z: 426.3 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 3.84 (s, 3H), 5.14(d, J=8.5 Hz, 1H), 7.08 (t, J=7.5 Hz, 1H), 7.15-7.40 (m, 4H), 7.42-7.58(m, 6H), 7.67 (td, J=7.4, 1.7 Hz, 2H), 8.98 (d, J=8.6 Hz, 1H), 10.98 (s,1H).

Example 10

Example 10 was prepared using a procedure similar to that used toprepare Example 1 where 5-(furan-2-yl)-1,3,4-oxadiazol-2(3H)-one wasused in place of5-(3-(2-methoxyethoxy)phenyl)-1,3,4-oxadiazol-2(3H)-one. ESI-MS m/z:386.1 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 5.14 (d, J=8.4 Hz, 1H), 6.72(dd, J=3.5, 1.8 Hz, 1H), 7.06 (dd, J=3.5, 0.8 Hz, 1H), 7.22-7.40 (m,3H), 7.40-7.61 (m, 5H), 7.66 (ddd, J=8.5, 7.0, 1.8 Hz, 1H), 7.94 (dd,J=1.8, 0.8 Hz, 1H), 9.21 (d, J=8.5 Hz, 1H), 10.99 (s, 1H).

Example 10a

Example 10a was separated from racemic Example 10 using a reverse phasechiral column (Gemini-NX C18 110A). ESI-MS m/z: 386.2 [M+H]⁺.

Example 10b

Example 10b was separated from racemic Example 10 using a reverse phasechiral column (Gemini-NX C18 110A). ESI-MS m/z: 386.2 [M+H]⁺.

Example 11

Example 11 was prepared using a procedure similar to that used toprepare Example 1 where 5-(pyridin-2-yl)-1,3,4-oxadiazol-2(3H)-one wasused in place of5-(3-(2-methoxyethoxy)phenyl)-1,3,4-oxadiazol-2(3H)-one. ESI-MS m/z:397.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 5.20 (d, J=8.5 Hz, 1H), 6.99(d, J=2.3 Hz, 1H), 7.12 (d, J=2.2 Hz, 1H), 7.22-7.33 (m, 2H), 7.33-7.42(m, 2H), 7.42-7.60 (m, 5H), 7.69 (ddd, J=8.5, 7.2, 1.7 Hz, 1H),7.94-8.05 (m, 2H), 8.71 (dt, J=4.7, 1.4 Hz, 1H), 9.32 (d, J=8.5 Hz, 1H),11.01 (s, 1H).

Example 12

Example 12 was prepared using a procedure similar to that used toprepare Example 1 where4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)benzonitrile was used in placeof 5-(3-(2-methoxyethoxy)phenyl)-1,3,4-oxadiazol-2(3H)-one. ESI-MS m/z:421.2 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 5.21 (d, J=8.1 Hz, 1H),7.23-7.42 (m, 3H), 7.42-7.61 (m, 5H), 7.69 (ddd, J=8.5, 7.0, 1.8 Hz,1H), 7.95-8.09 (m, 4H), 9.37 (d, J=8.3 Hz, 1H), 11.02 (s, 1H).

Example 13

Example 13 was prepared using a procedure similar to that used toprepare Example 1 where 5-(4-chlorophenyl)-1,3,4-oxadiazol-2(3H)-one wasused in place of5-(3-(2-methoxyethoxy)phenyl)-1,3,4-oxadiazol-2(3H)-one. ESI-MS m/z:430.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 5.18 (d, J=8.5 Hz, 1H),7.23-7.41 (m, 3H), 7.41-7.60 (m, 5H), 7.61-7.75 (m, 3H), 7.79-7.89 (m,2H), 9.20 (d, J=8.5 Hz, 1H), 11.00 (s, 1H).

Example 14

Example 14 was prepared using a procedure similar to that used toprepare Example 1 where5-(4-fluoro-3-methoxyphenyl)-1,3,4-oxadiazol-2(3H)-one was used in placeof 5-(3-(2-methoxyethoxy)phenyl)-1,3,4-oxadiazol-2(3H)-one. ESI-MS m/z:444.2 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 3.94 (s, 3H), 5.18 (d, J=8.4Hz, 1H), 7.23-7.63 (m, 11H), 7.69 (ddd, J=8.4, 7.0, 1.7 Hz, 1H), 9.12(d, J=8.5 Hz, 1H), 11.01 (s, 1H).

Example 15

Example 15 was prepared using a procedure similar to that used toprepare Example 1 where 5-(3-isopropoxyphenyl)-1,3,4-oxadiazol-2(3H)-onewas used in place of5-(3-(2-methoxyethoxy)phenyl)-1,3,4-oxadiazol-2(3H)-one. ESI-MS m/z:454.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 1.30 (d, J=5.9 Hz, 6H), 4.68(p, J=6.0 Hz, 1H), 5.17 (d, J=8.4 Hz, 1H), 7.10 (ddd, J=8.2, 2.6, 1.0Hz, 1H), 7.25-7.32 (m, 2H), 7.33-7.41 (m, 3H), 7.42-7.58 (m, 6H), 7.68(ddd, J=8.3, 7.2, 1.7 Hz, 1H), 9.09 (d, J=8.4 Hz, 1H), 11.00 (s, 1H).

Example 16

Example 16 was prepared using a procedure similar to that used toprepare Example 1 where 5-(naphthalen-2-yl)-1,3,4-oxadiazol-2(3H)-onewas used in place of5-(3-(2-methoxyethoxy)phenyl)-1,3,4-oxadiazol-2(3H)-one. ESI-MS m/z:446.3 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 5.22 (d, J=8.4 Hz, 1H),7.24-7.42 (m, 3H), 7.44-7.60 (m, 5H), 7.60-7.76 (m, 3H), 7.92-8.07 (m,2H), 8.11 (dd, J=8.0, 4.9 Hz, 2H), 8.34-8.45 (m, 1H), 9.21 (d, J=8.5 Hz,1H), 11.03 (s, 1H).

Example 17

Example 17 was prepared using a procedure similar to that used toprepare Example 1 where 5-(naphthalen-1-yl)-1,3,4-oxadiazol-2(3H)-onewas used in place of5-(3-(2-methoxyethoxy)phenyl)-1,3,4-oxadiazol-2(3H)-one. ESI-MS m/z:446.3[M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 5.25 (d, J=8.4 Hz, 1H),7.24-7.43 (m, 3H), 7.43-7.61 (m, 5H), 7.60-7.77 (m, 4H), 8.07 (td,J=7.6, 1.7 Hz, 2H), 8.15 (d, J=8.2 Hz, 1H), 9.02-9.13 (m, 1H), 9.23 (d,J=8.4 Hz, 1H), 11.03 (s, 1H).

Example 18

Example 18 was prepared using a procedure similar to that used toprepare Example 1 where 5-methyl-1,3,4-oxadiazol-2(3H)-one was used inplace of 5-(3-(2-methoxyethoxy)phenyl)-1,3,4-oxadiazol-2(3H)-one. ESI-MSm/z: 334.2 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 2.32 (s, 3H), 5.03 (d,J=8.7 Hz, 1H), 7.20-7.37 (m, 3H), 7.38-7.60 (m, 5H), 7.65 (ddd, J=8.6,7.0, 1.8 Hz, 1H), 8.73 (d, J=8.7 Hz, 1H), 10.92 (s, 1H).

Example 19

Example 19 was prepared using a procedure similar to that used toprepare Example 1 where5-(5-methylthiophen-2-yl)-1,3,4-oxadiazol-2(3H)-one was used in place of5-(3-(2-methoxyethoxy)phenyl)-1,3,4-oxadiazol-2(3H)-one. ESI-MS m/z:416.3 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 2.52 (s, 3H), 5.14 (d, J=8.5Hz, 1H), 6.95 (dd, J=3.6, 1.3 Hz, 1H), 7.23-7.61 (m, 9H), 7.68 (m, 1H),9.11 (d, J=8.5 Hz, 1H), 10.99 (s, 1H).

Example 20

Example 20 Step a

A solution of (Z)-3-amino-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one(5.1 g, 20.3 mmol), 1,1′-thiocarbonyldiimidazole (5.4 g, 30.3 mmol) inDMF (20 mL) was stirred for 20 minutes before hydrazinemonohydrate (2mL) was added. The mixture was stirred for 30 minutes, diluted withEtOAc, and washed with water (×2). The organic layer was dried (Na₂SO₄)and concentrated to give desired compound as a light yellow solid (5 g,76%) that was used without further purification. ESI-MS m/z: 326.1[M+H]⁺.

Example 20 Step b

A solution of the compound from step a (100 mg, 0.3 mmol),5-chlorofuran-2-carboxylic acid (54 mg, 0.4 mmol), HOBt (61 mg, 0.48mmol) and EDCI (86 mg, 0.45 mmol) in DMF (2 mL) was stirred for 2 hours.The mixture was purified by reverse phase C18 column chromatography(MeCN:H₂O) to give desired compound as a white solid (110 mg, 80%).ESI-MS m/z: 454.2 [M+H]⁺.

Example 20 Step c

A solution of the compound from step b (110 mg, 0.24 mmol) and EDCI (70mg, 0.36 mmol) in DMF (5 mL) was stirred for 30 minutes at 60° C. It waspurified by prep-HPLC to give the title compound as a yellow solid (27mg, 27%). ESI-MS m/z: 420.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 5.15 (d,J=8.4 Hz, 1H), 6.79 (d, J=3.6 Hz, 1H), 7.17 (d, J=3.6 Hz, 1H), 7.23-7.39(m, 3H), 7.50 (m, 5H), 7.62-7.72 (m, 1H), 9.28 (d, J=8.4 Hz, 1H), 10.99(s, 1H).

Example 21

Example 21 Step a

A solution of (Z)-3-amino-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one(200 mg, 0.8 mmol), 1,1′-thiocarbonyldiimidazole (178 mg, 1.0 mmol) inDMF (3 mL) was stirred for 20 minutes beforetetrahydro-2H-pyran-4-carbohydrazide (159 mg, 1.1 mmol) was added. Theresulting mixture was stirred for 30 minutes and used directly in thenext step. ESI-MS m/z: 438.2 [M+H]⁺.

Example 21 Step b

A solution of the compound from step a (350 mg, 0.8 mmol) and EDCI (192mg, 1.0 mmol) in DMF (3 mL) was stirred for 60 minutes at 60° C. It waspurified by directly by prep-HPLC to give the title compound as a whitesolid (54 mg, 17%). ESI-MS m/z: 404.2 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆)δ 1.69 (tdd, J=13.2, 10.9, 5.5 Hz, 2H), 1.80-1.95 (m, 2H), 3.09 (tt,J=10.9, 4.0 Hz, 1H), 3.45 (td, J=11.3, 2.3 Hz, 2H), 3.88 (dt, J=11.6,3.6 Hz, 2H), 5.07 (d, J=8.2 Hz, 1H), 7.21-7.40 (m, 3H), 7.41-7.61 (m,5H), 7.67 (ddd, J=8.5, 7.0, 1.8 Hz, 1H), 8.81 (d, J=8.7 Hz, 1H), 10.95(s, 1H).

Example 22

Example 22 was prepared using a procedure similar to that used toprepare Example 21 where 2-phenylacetohydrazide was used in place oftetrahydro-2H-pyran-4-carbohydrazide. ESI-MS m/z: 410.2 [M+H]⁺. ¹H NMR(300 MHz, DMSO-d₆) δ 4.11 (s, 2H), 5.05 (d, J=8.6 Hz, 1H), 7.23-7.41 (m,8H), 7.43-7.57 (m, 5H), 7.67 (ddd, J=8.5, 6.9, 1.9 Hz, 1H), 8.78 (d,J=8.7 Hz, 1H), 10.85-11.02 (m, 1H).

Example 23

Example 23 was prepared using a procedure similar to that used toprepare Example 20 where 5-fluoropicolinic acid was used in place of5-chlorofuran-2-carboxylic acid ESI-MS m z: 415.0 [M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 5.20 (d, J=7.9 Hz, 1H), 7.24-7.61 (m, 8H), 7.69 (m, 1H),7.94 (m, 1H), 8.09 (dd, J=8.8, 4.4 Hz, 1H), 8.74 (d, J=2.8 Hz, 1H), 9.32(d, J=8.4 Hz, 1H), 10.96 (s, 1H).

Example 24

Example 24 was prepared using a procedure similar to that used toprepare Example 20 where 5-cyanopicolinic acid was used in place of5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 422.3 [M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 5.23 (d, J=7.5 Hz, 1H), 7.24-7.42 (m, 3H), 7.52 (dq,J=12.0, 6.8, 5.5 Hz, 5H), 7.70 (t, J=7.3 Hz, 1H), 8.16 (d, J=8.3 Hz,1H), 8.48 (dd, J=8.3, 2.1 Hz, 1H), 9.13-9.22 (m, 1H), 9.58 (d, J=8.3 Hz,1H), 11.04 (s, 1H).

Example 25

Example 25 was prepared using a procedure similar to that used toprepare Example 20 where 5-(trifluoromethyl)picolinic acid was used inplace of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 465.3 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 5.21 (d, J=7.6 Hz, 1H), 7.22-7.41 (m, 3H),7.39-7.60 (m, 5H), 7.68 (m, 1H), 8.18 (d, J=8.4 Hz, 1H), 8.38 (m, 1H),9.11 (m, 1H), 9.52 (d, J=8.3 Hz, 1H), 11.01 (s, 1H).

Example 26

Example 26 was prepared using a procedure similar to that used toprepare Example 20 where 6-methylpicolinic acid was used in place of5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 411.1 [M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 2.54 (s, 3H), 5.18 (d, J=8.5 Hz, 1H), 7.21-7.75 (m,10H), 7.74-7.92 (m, 2H), 9.27 (d, J=8.5 Hz, 1H), 10.99 (s, 1H).

Example 27

Example 27 was prepared using a procedure similar to that used toprepare Example 21 where 4-(methyl sulfonyl)benzohydrazide was used inplace of tetrahydro-2H-pyran-4-carbohydrazide. ESI-MS m/z: 474.2 [M+H]⁺.¹H NMR (300 MHz, DMSO-d₆) δ 5.21 (s, 1H), 7.23-7.43 (m, 3H), 7.43-7.61(m, 5H), 7.69 (ddd, J=8.4, 7.0, 1.7 Hz, 1H), 8.02-8.19 (m, 4H), 9.37 (s,1H), 10.96 (s, 1H).

Example 28

Example 28 was prepared using a procedure similar to that used toprepare Example 20 where 4-(trifluoromethyl)benzoic acid was used inplace of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 464.1 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 5.19 (d, J=11.2 Hz, 1H), 7.20-7.60 (m, 8H),7.65-7.75 (m, 1H), 7.90-8.00 (m, 2H), 8.00-8.10 (m, 2H), 9.34 (d, J=11.2Hz, 1H), 11.02 (s, 1H).

Example 29

Example 29 was prepared using a procedure similar to that used toprepare Example 20 where 3-(trifluoromethyl)benzoic acid was used inplace of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 464.3 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 5.19 (d, J=11.2 Hz, 1H), 7.20-7.40 (m, 3H),7.40-7.60 (m, 5H), 7.65-7.75 (m, 1H), 7.90-8.00 (m, 2H), 8.00-8.10 (m,2H), 9.30-9.40 (d, J=11.6 Hz, 1H), 11.02 (s, 1H).

Example 30

Example 30 was prepared using a procedure similar to that used toprepare Example 20 where 4-(trifluoromethoxy)benzoic acid was used inplace of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 480.2 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 5.17 (d, J=8.4 Hz, 1H), 7.22-7.61 (m, 11H),7.67 (m, 1H), 7.88-8.00 (m, 2H), 9.23 (d, J=8.5 Hz, 1H), 11.00 (s, 1H).

Example 31

Example 31 was prepared using a procedure similar to that used toprepare Example 20 where 4-sulfamoylbenzoic acid was used in place of5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 475.3 [M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 5.19 (s, 1H), 7.20-7.80 (m, 12H), 7.90-8.10 (m, 4H),9.20-9.60 (m, 1H).

Example 32

Example 32 was prepared using a procedure similar to that used toprepare Example 20 where 3-cyano-4-fluorobenzoic acid was used in placeof 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 439.1 [M+H]⁺. ¹H NMR(300 MHz, DMSO-d₆) δ 5.18 (d, J=8.2 Hz, 1H), 7.26-7.60 (m, 8H), 7.71(dt, J=14.3, 7.9 Hz, 2H), 8.17 (m, 1H), 8.30 (dd, J=6.0, 2.3 Hz, 1H),9.30 (d, J=8.4 Hz, 1H), 11.02 (s, 1H).

Example 33

Example 33 was prepared using a procedure similar to that used toprepare Example 20 where 4-cyano-3-fluorobenzoic acid was used in placeof 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 439.1 [M+H]⁺. ¹H NMR(300 MHz, DMSO-d₆) δ 5.19 (s, 1H), 7.22-7.59 (m, 9H), 7.67 (m, 1H), 7.82(m, 2H), 8.12 (dd, J=8.1, 6.7 Hz, 1H), 9.49 (s, 1H), 11.01 (s, 1H).

Example 34

Example 34 was prepared using a procedure similar to that used toprepare Example 20 where 4-cyano-3-methylbenzoic acid was used in placeof 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 435.2 [M+H]⁺. ¹H NMR(300 MHz, DMSO-d₆) δ 2.57 (s, 3H), 5.19 (d, J=8.3 Hz, 1H), 7.23-7.60 (m,8H), 7.62-7.81 (m, 2H), 7.87-8.00 (m, 2H), 9.36 (d, J=8.4 Hz, 1H), 11.03(s, 1H).

Example 35

Example 35 was prepared using a procedure similar to that used toprepare Example 20 where 3-cyanobenzoic acid was used in place of5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 421.3 [M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 5.20 (s, 1H), 7.25-7.33 (m, 1H), 7.37 (dd, J=8.1, 2.2Hz, 2H), 7.43-7.60 (m, 5H), 7.69 (ddd, J=8.4, 7.1, 1.7 Hz, 1H), 7.79 (t,J=7.9 Hz, 1H), 8.03 (dt, J=7.7, 1.4 Hz, 1H), 8.14 (dt, J=8.0, 1.4 Hz,1H), 8.20 (t, J=1.6 Hz, 1H), 9.31 (s, 1H), 11.03 (s, 1H).

Example 36

Example 36 was prepared using a procedure similar to that used toprepare Example 20 where 4-(1H-pyrazol-1-yl)benzoic acid was used inplace of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 462.3 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 5.19 (d, J=8.4 Hz, 1H), 6.62 (t, J=2.2 Hz, 1H),7.24-7.42 (m, 3H), 7.43-7.62 (m, 5H), 7.70 (ddd, J=8.4, 7.1, 1.7 Hz,1H), 7.83 (d, J=1.7 Hz, 1H), 7.89-8.01 (m, 2H), 8.02-8.12 (m, 2H), 8.63(d, J=2.6 Hz, 1H), 9.18 (d, J=8.6 Hz, 1H), 11.01 (s, 1H).

Example 37

Example 37 was prepared using a procedure similar to that used toprepare Example 20 where nicotinic acid was used in place of5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 397.2 [M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 5.19 (d, J=8.4 Hz, 1H), 7.23-7.74 (m, 10H), 8.14-8.23(m, 1H), 8.72 (d, J=4.7 Hz, 1H), 9.01 (s, 1H), 9.26 (d, J=8.4 Hz, 1H),11.01 (s, 1H).

Example 38

Example 38 was prepared using a procedure similar to that used toprepare Example 20 where 2-cyanoisonicotinic acid was used in place of5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 422.3 [M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 5.24 (s, 1H), 7.16-7.43 (m, 3H), 7.52 (hept, J=7.6, 7.0Hz, 5H), 7.70 (t, J=7.3 Hz, 1H), 8.03 (dd, J=5.1, 1.8 Hz, 1H), 8.33 (s,1H), 8.50 (s, OH), 8.93 (d, J=5.2 Hz, 1H), 9.61 (s, 1H), 11.09 (s, 1H).

Example 39

Example 39 was prepared using a procedure similar to that used toprepare Example 20 where 6-oxo-1,6-dihydropyridine-3-carboxylic acid wasused in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 413.2[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 5.13 (d, J=8.6 Hz, 1H), 6.45-6.53(m, 1H), 7.24-7.39 (m, 3H), 7.42-7.59 (m, 5H), 7.68 (m, 1H), 7.76-7.84(m, 2H), 9.00 (d, J=8.7 Hz, 1H), 11.01 (s, 1H), 12.05 (s, 1H).

Example 40

Example 40 was prepared using a procedure similar to that used toprepare Example 20 where 2-oxo-1,2-dihydropyridine-4-carboxylic acid wasused in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 413.2[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 5.18 (s, 1H), 6.53-6.63 (m, 2H),7.24-7.40 (m, 3H), 7.42-7.59 (m, 6H), 7.68 (m, 1H), 9.41 (s, 1H), 11.39(s, 2H).

Example 41

Example 41 was prepared using a procedure similar to that used toprepare Example 20 where 1H-benzo[d]imidazole-6-carboxylic acid was usedin place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 436.3 [M+H]⁺.¹H NMR (300 MHz, DMSO-d₆) δ 5.17 (d, J=11.6 Hz, 1H), 7.20-7.40 (m, 3H),7.40-7.60 (m, 5H), 7.60-7.85 (m, 3H), 8.01 (s, 1H), 8.37 (s, 1H), 9.06(d, J=11.6 Hz, 1H), 11.02 (s, 1H).

Example 42

Example 42 was prepared using a procedure similar to that used toprepare Example 20 where benzo[d]thiazole-6-carboxylic acid was used inplace of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 453.2 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 5.21 (d, J=8.4 Hz, 1H), 7.24-7.62 (m, 9H), 7.70(ddd, J=8.5, 7.2, 1.8 Hz, 1H), 8.00 (dd, J=8.6, 1.8 Hz, 1H), 8.25 (d,J=8.6 Hz, 1H), 8.69 (d, J=1.7 Hz, 1H), 9.26 (d, J=8.5 Hz, 1H), 9.54 (s,1H), 11.02 (s, 1H).

Example 43

Example 43 was prepared using a procedure similar to that used toprepare Example 20 where thieno[2,3-b]pyridine-2-carboxylic acid wasused in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 453.1[M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 2.53 (s, 2H), 5.19 (d, J=6.3 Hz,1H), 7.21-7.59 (m, 9H), 7.68 (ddd, J=8.4, 7.0, 1.7 Hz, 1H), 7.92-8.01(m, 2H), 8.55 (d, J=5.5 Hz, 1H), 9.33 (t, J=0.9 Hz, 1H), 9.53 (s, 1H),11.03 (s, 1H).

Example 44

Example 44 was prepared using a procedure similar to that used toprepare Example 20 where5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid wasused in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 472.2[M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 2.40 (s, 3H), 2.81 (dt, J=28.9, 5.9Hz, 4H), 3.68 (s, 2H), 5.17 (d, J=8.3 Hz, 1H), 7.22-7.60 (m, 8H),7.65-7.70 (m, 1H), 9.44 (d, J=8.3 Hz, 1H), 11.00 (s, 1H).

Example 45

Example 45 was prepared using a procedure similar to that used toprepare Example 21 where piperidine-4-carbohydrazide was used in placeof tetrahydro-2H-pyran-4-carbohydrazide. ESI-MS m/z: 403.2 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 1.75-1.93 (m, 2H), 2.04-2.18 (m, 2H), 3.04 (q,J=11.2 Hz, 2H), 3.20 (tt, J=10.9, 4.0 Hz, 1H), 3.33 (d, J=13.2 Hz, 2H),5.07 (d, J=8.4 Hz, 1H), 7.23-7.41 (m, 3H), 7.41-7.60 (m, 5H), 7.67 (ddd,J=8.4, 7.0, 1.8 Hz, 1H), 8.55 (d, J=10.8 Hz, 1H), 8.87 (d, J=8.7 Hz,2H), 10.97 (s, 1H).

Example 46

Example 46 was prepared using a procedure similar to that used toprepare Example 20 where 1-methylpiperidine-4-carboxylic acid was usedin place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 417.3 [M+H]⁺.¹H NMR (300 MHz, DMSO-d₆) δ 1.58-1.76 (m, 2H), 1.85-1.97 (m, 2H),1.97-2.11 (m, 2H), 2.20 (s, 3H), 2.77 (td, J=10.9, 5.3 Hz, 3H), 5.06 (d,J=8.7 Hz, 1H), 7.18-7.40 (m, 3H), 7.41-7.60 (m, 5H), 7.67 (ddd, J=8.5,7.0, 1.8 Hz, 1H), 8.75 (d, J=8.7 Hz, 1H), 10.94 (s, 1H).

Example 47

Example 47 was prepared using a procedure similar to that used toprepare Example 21 where 1-acetylpiperidine-4-carbohydrazide was used inplace of tetrahydro-2H-pyran-4-carbohydrazide. ESI-MS m/z: 445.3 [M+H]⁺.¹H NMR (300 MHz, DMSO-d₆) δ 1.26-1.26 (m, 2H), 1.92-2.09 (m, 4H),2.72-2.88 (m, 1H), 3.03-3.28 (m, 2H), 4.25 (d, J=13.3 Hz, 1H), 5.07 (d,J=7.8 Hz, 1H), 7.31 (dtd, J=15.2, 7.9, 5.4 Hz, 2H), 7.40-7.61 (m, 4H),7.67 (ddd, J=8.4, 7.0, 1.8 Hz, 1H), 8.83 (d, J=8.7 Hz, 1H), 10.95 (s,1H).

Example 48

Example 48 was prepared using a procedure similar to that used toprepare Example 20 where(S)-4-(tert-butoxycarbonyl)morpholine-3-carboxylic acid was used inplace of 5-chlorofuran-2-carboxylic acid. The Boc-protected intermediate(126 mg, 0.5 mmol) was dissolved in DCM (20 mL) and then HCl (gas)saturated dioxane (10 mL) was added to the mixture and it was stirred atr.t for 2 h. Solid K₂CO₃ was added to neutralize the HCl, and the solidwas filtered off. The filtrate was concentrated and the resultingresidue was purified by prep-HPLC to give the title compound as a whitesolid (49 mg, 48%). ESI-MS m/z: 405.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆)δ 2.70-2.81 (m, 1H), 2.83-2.95 (m, 2H), 3.49 (m, 1H), 3.63 (m, 2H), 3.86(m, 1H), 3.97 (dd, J=8.3, 3.2 Hz, 1H), 5.07 (dd, J=8.6, 1.4 Hz, 1H),7.23-7.38 (m, 3H), 7.41-7.58 (m, 5H), 7.66 (m, 1H), 8.86 (dd, J=8.7, 1.7Hz, 1H), 10.94 (s, 1H).

Example 49

Example 49 was prepared using a procedure similar to that used toprepare Example 20 where(R)-4-(tert-butoxycarbonyl)morpholine-3-carboxylic acid was used inplace of 5-chlorofuran-2-carboxylic acid. The Boc-protected intermediatewas de-protected using a procedure similar to that described in Example48. ESI-MS m/z: 405.0 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 2.66-2.81 (m,1H), 2.86 (d, J=13.1 Hz, 1H), 3.41-3.71 (m, 3H), 3.79-3.90 (m, 1H), 3.96(m, 1H), 5.06 (m, 1H), 7.20-7.38 (m, 3H), 7.38-7.58 (m, 5H), 7.65 (m,1H), 8.45 (S, 0.23H), 8.79-8.89 (m, 1H), 10.94 (d, J=6.0 Hz, 1H).

Example 50

Example 50 was prepared using a procedure similar to that used toprepare Example 20 where 2,4-difluorobenzoic acid was used in place of5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 432.2 [M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 5.18 (d, J=8.4 Hz, 1H), 7.20-7.61 (m, 10H), 7.61-7.77(m, 1H), 7.92 (td, J=8.6, 6.3 Hz, 1H), 9.22 (d, J=8.5 Hz, 1H), 11.01 (s,1H).

Example 51

Example 51 was prepared using a procedure similar to that used toprepare Example 20 where 5-methoxypicolinic acid was used in place of5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 427.3 [M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 3.91 (s, 3H), 5.17 (d, J=8.5 Hz, 1H), 7.22-7.61 (m, 9H),7.68 (m, 1H), 7.95 (d, J=8.8 Hz, 1H), 8.41 (d, J=2.9 Hz, 1H), 9.18 (d,J=8.6 Hz, 1H), 11.00 (s, 1H).

Example 52

Example 52 was prepared using a procedure similar to that used toprepare Example 20 where 6-methoxypicolinic acid was used in place of5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 427.1 [M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 3.91 (s, 3H), 5.18 (d, J=8.4 Hz, 1H), 6.97 (dd, J=8.4,0.8 Hz, 1H), 7.21-7.73 (m, 10H), 7.87 (dd, J=8.4, 7.4 Hz, 1H), 9.28 (d,J=8.5 Hz, 1H), 10.99 (s, 1H).

Example 53

Example 53 was prepared using a procedure similar to that used toprepare Example 20 where 6-fluoronicotinic acid was used in place of5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 415.3 [M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 5.17 (d, J=8.4 Hz, 1H), 7.22-7.59 (m, 9H), 7.67 (m, 1H),8.21 (s, 0.518H), 8.37 (m, 1H), 8.66 (d, J=2.4 Hz, 1H), 9.28 (d, J=8.4Hz, 1H), 11.01 (s, 1H).

Example 54

Example 54 was prepared using a procedure similar to that used toprepare Example 20 where 6-methoxynicotinic acid was used in place of5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 427.3 [M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 3.93 (s, 3H), 5.16 (d, J=8.2 Hz, 1H), 7.01 (d, J=8.7 Hz,1H), 7.22-7.59 (m, 8H), 7.65-7.70 (m, 1H), 8.10 (dd, J=8.7, 2.5 Hz, 1H),8.61 (d, J=2.4 Hz, 1H), 9.14 (d, J=8.5 Hz, 1H), 10.97 (s, 1H).

Example 55

Example 55 was prepared using a procedure similar to that used toprepare Example 20 where 2-fluoroisonicotinic acid was used in place of5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 415.3 [M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 5.20 (s, 1H), 7.22-7.76 (m, 11H), 8.44 (d, J=5.2 Hz,1H). 9.48 (s, 1H), 11.00 (s, 1H).

Example 56

Example 56 was prepared using a procedure similar to that used toprepare Example 20 where 2-methoxyisonicotinic acid was used in place of5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 427.1 [M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 3.91 (s, 3H), 5.18 (d, J=8.2 Hz, 1H), 7.07 (t, J=1.0 Hz,1H), 7.22-7.59 (m, 9H), 7.67 (ddd, J=8.4, 7.0, 1.8 Hz, 1H), 8.34 (d,J=5.3 Hz, 1H), 9.38 (d, J=8.4 Hz, 1H), 11.02 (s, 1H).

Example 57

Example 57 was prepared using a procedure similar to that used toprepare Example 20 where 4-methoxypicolinic acid was used in place of5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 427.2 [M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 3.91 (s, 3H), 5.19 (d, J=8.4 Hz, 1H), 7.12 (dd, J=5.8,2.5 Hz, 1H), 7.22-7.59 (m, 9H), 7.68 (m, 1H), 8.51 (d, J=5.7 Hz, 1H),9.27 (d, J=8.5 Hz, 1H), 10.97-11.04 (m, 1H).

Example 58

Example 58 was prepared using a procedure similar to that used toprepare Example 20 where pyrazine-2-carboxylic acid was used in place of5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 398.2 [M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 5.20 (d, J=8.1 Hz, 1H), 7.22-7.59 (m, 8H), 7.67 (m, 1H),8.72-8.82 (m, 2H), 9.19 (d, J=1.3 Hz, 1H), 9.46 (d, J=8.3 Hz, 1H), 11.01(s, 1H).

Example 59

Example 59 was prepared using a procedure similar to that used toprepare Example 20 where pyrimidine-2-carboxylic acid was used in placeof 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 398.2 [M+H]⁺. ¹H NMR(300 MHz, DMSO-d₆) δ 5.23 (d, J=8.4 Hz, 1H), 7.23-7.43 (m, 3H),7.43-7.62 (m, 5H), 7.60-7.77 (m, 2H), 8.98 (d, J=4.9 Hz, 2H), 9.47 (d,J=8.4 Hz, 1H), 11.01 (s, 1H).

Example 60

Example 60 was prepared using a procedure similar to that used toprepare Example 20 where pyrimidine-5-carboxylic acid was used in placeof 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 398.1 [M+H]⁺. ¹H NMR(300 MHz, DMSO-d₆) δ 5.20 (d, J=7.7 Hz, 1H), 7.21-7.59 (m, 8H), 7.67 (m,1H), 9.17 (s, 2H), 9.35 (d, J=19.3 Hz, 2H), 11.00 (s, 1H).

Example 61

Example 61 was prepared using a procedure similar to that used toprepare Example 20 where isonicotinic acid was used in place of5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 397.1 [M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 5.21 (d, J=8.3 Hz, 1H), 7.24-7.61 (m, 8H), 7.63-7.80 (m,3H), 8.73-8.88 (m, 2H), 9.41 (d, J=8.4 Hz, 1H), 11.02 (s, 1H).

Example 62

Example 62 was prepared using a procedure similar to that used toprepare Example 20 where pyridazine-3-carboxylic acid was used in placeof 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 398.2 [M+H]⁺. ¹H NMR(300 MHz, DMSO-d₆) δ 5.24 (d, J=8.2 Hz, 1H), 7.24-7.43 (m, 3H),7.43-7.62 (m, 5H), 7.70 (ddd, J=8.4, 7.0, 1.7 Hz, 1H), 7.89 (dd, J=8.6,5.0 Hz, 1H), 8.25 (dd, J=8.6, 1.6 Hz, 1H), 9.36 (dd, J=5.0, 1.6 Hz, 1H),9.55 (d, J=8.4 Hz, 1H), 11.04 (s, 1H).

Example 63

Example 63 was prepared using a procedure similar to that used toprepare Example 20 where pyrimidine-4-carboxylic acid was used in placeof 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 398.1 [M+H]⁺. ¹H NMR(300 MHz, DMSO-d₆) δ 5.23 (s, 1H), 7.24-7.62 (m, 8H), 7.69 (m, 1H), 8.02(dd, J=5.3, 1.5 Hz, 1H), 8.99 (d, J=5.3 Hz, 1H), 9.34 (d, J=1.4 Hz, 1H),9.60 (s, 1H), 11.03 (s, 1H).

Example 64

Example 64 was prepared using a procedure similar to that used toprepare Example 20 where 6-(methoxymethyl)picolinic acid was used inplace of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 441.1 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 3.40 (s, 3H), 4.57 (s, 2H), 5.19 (d, J=8.4 Hz,1H), 7.22-7.59 (m, 10H), 7.68 (m, 1H), 7.86-8.05 (m, 2H), 9.29 (d, J=8.5Hz, 1H), 10.98 (s, 1H).

Example 65

Example 65 was prepared using a procedure similar to that used toprepare Example 20 where 1-methyl-1H-pyrazole-5-carboxylic acid was usedin place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 400.2 [M+H]⁺.¹H NMR (300 MHz, DMSO-d₆) δ 4.11 (s, 3H), 5.17 (d, J=8.2 Hz, 1H), 6.74(d, J=2.0 Hz, 1H), 7.22-7.74 (m, 10H), 9.24 (d, J=8.4 Hz, 1H), 11.00 (s,1H).

Example 66

Example 66 was prepared using a procedure similar to that used toprepare Example 20 where 1-methyl-1H-pyrazole-4-carboxylic acid was usedin place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 400.3 [M+H]⁺.¹H NMR (300 MHz, DMSO-d₆) δ 3.92 (s, 3H), 5.12 (d, J=8.6 Hz, 1H),7.21-7.60 (m, 8H), 7.67 (m, 1H), 7.84 (d, J=0.8 Hz, 1H), 8.28 (s, 1H),8.92 (d, J=8.6 Hz, 1H), 10.96 (s, 1H).

Example 67

Example 67 was prepared using a procedure similar to that used toprepare Example 20 where 1-methyl-1H-imidazole-2-carboxylic acid wasused in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 400.3[M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 3.92 (s, 3H), 5.15 (d, J=8.1 Hz,1H), 7.09 (d, J=1.1 Hz, 1H), 7.21-7.59 (m, 9H), 7.67 (m, 1H), 9.24 (d,J=8.5 Hz, 1H), 10.96 (s, 1H).

Example 68

Example 68 was prepared using a procedure similar to that used toprepare Example 20 where 1-methyl-1H-imidazole-4-carboxylic acid wasused in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 400.3[M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 3.72 (s, 3H), 5.12 (d, J=8.6 Hz,1H), 7.21-7.59 (m, 8H), 7.60-7.79 (m, 3H), 8.91 (d, J=8.7 Hz, 1H), 10.97(s, 1H).

Example 69

Example 69 was prepared using a procedure similar to that used toprepare Example 20 where thiazole-2-carboxylic acid was used in place of5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 403.0 [M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 5.20 (s, 1H), 7.23-7.61 (m, 8H), 7.69 (m, 1H), 7.99-8.15(m, 2H), 9.50 (s, 1H), 11.02 (s, 1H).

Example 70

Example 70 was prepared using a procedure similar to that used toprepare Example 20 where oxazole-2-carboxylic acid was used in place of5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 387.4 [M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 3.34 (d, J=14.0 Hz, 1H), 5.20 (d, J=8.3 Hz, 1H),7.22-7.62 (m, 10H), 7.69 (ddd, J=8.4, 7.1, 1.8 Hz, 1H), 8.41 (d, J=0.8Hz, 1H), 9.61 (d, J=8.3 Hz, 1H), 11.03 (s, 1H).

Example 71

Example 71 was prepared using a procedure similar to that used toprepare Example 20 where 5-methylfuran-2-carboxylic acid was used inplace of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 400.0 [M+H]⁺. 1HNMR (300 MHz, DMSO-d₆) δ 2.39 (s, 3H), 5.14 (d, J=8.5 Hz, 1H), 6.36 (dd,J=3.3, 1.2 Hz, 1H), 6.95 (d, J=3.3 Hz, 1H), 7.23-7.61 (m, 8H), 7.68 (m,1H), 9.13 (d, J=8.5 Hz, 1H), 10.98 (s, 1H).

Example 72

Example 72 was prepared using a procedure similar to that used toprepare Example 20 where 5-(methoxymethyl)furan-2-carboxylic acid wasused in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 430.1[M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 3.28 (s, 3H), 4.44 (s, 2H), 5.14 (s,1H), 6.68 (d, J=3.5 Hz, 1H), 7.02 (d, J=3.4 Hz, 1H), 7.21-7.59 (m, 8H),7.67 (m, 1H), 9.26 (s, 2H).

Example 73

Example 73 was prepared using a procedure similar to that used toprepare Example 20 where 5-((dimethylamino)methyl)furan-2-carboxylicacid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z:443.3 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 2.79 (s, 6H), 4.50 (s, 2H),5.15 (d, J=8.4 Hz, 1H), 6.94 (d, J=3.5 Hz, 1H), 7.13 (d, J=3.5 Hz, 1H),7.22-7.60 (m, 8H), 7.61-7.74 (m, 1H), 9.30 (d, J=8.5 Hz, 1H), 10.33 (s,1H), 10.99 (s, 1H).

Example 74

Example 74 was prepared using a procedure similar to that used toprepare Example 20 where 3-methylisoxazole-5-carboxylic acid was used inplace of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 401.2 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 2.34 (s, 3H), 5.16 (s, 1H), 7.02 (s, 1H),7.23-7.36 (m, 3H), 7.43-7.56 (m, 5H), 7.66 (t, J=7.4 Hz, 1H), 9.76 (s,1H), 10.89 (s, 1H).

Example 75

Example 75 was prepared using a procedure similar to that used toprepare Example 20 where oxazole-5-carboxylic acid was used in place of5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 387.2 [M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 5.17 (d, J=8.3 Hz, 1H), 7.23-7.43 (m, 3H), 7.43-7.63 (m,5H), 7.69 (td, J=7.7, 7.0, 1.8 Hz, 1H), 7.85 (s, 1H), 8.69 (s, 1H), 9.41(d, J=8.4 Hz, 1H), 11.01 (s, 1H).

Example 76

Example 76 was prepared using a procedure similar to that used toprepare Example 20 where thiazole-5-carboxylic acid was used in place of5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 403.2 [M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 5.15 (d, J=8.2 Hz, 1H), 7.21-7.59 (m, 8H), 7.66 (m, 1H),8.35 (s, 1H), 9.27 (d, J=7.9 Hz, 2H), 10.99 (s, 1H).

Example 77

Example 77 was prepared using a procedure similar to that used toprepare Example 20 where thiazole-4-carboxylic acid was used in place of5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 403.2 [M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 5.18 (d, J=8.5 Hz, 1H), 7.20-7.43 (m, 3H), 7.42-7.61 (m,5H), 7.69 (ddd, J=8.5, 7.0, 1.7 Hz, 1H), 8.33 (d, J=1.9 Hz, 1H), 9.20(d, J=8.5 Hz, 1H), 9.30 (d, J=1.9 Hz, 1H), 10.99 (s, 1H).

Example 78

Example 78 was prepared using a procedure similar to that used toprepare Example 20 where 2-ethoxy-2-oxoacetic acid was used in place of5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 392.21 [M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 1.31 (t, J=7.1 Hz, 3H), 4.36 (q, J=7.1 Hz, 2H), 5.18 (s,1H), 7.22-7.40 (m, 3H), 7.40-7.60 (m, 5H), 7.64-7.70 (m, 1H), 9.70 (s,1H), 11.04 (s, 1H).

Example 79

Example 79 Step a

A solution of (Z)-3-amino-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one(300 mg, 1.195 mmol), BTC (116.7 mg, 0.394 mmol) and saturated NaHCO₃ (3mL) in DCM (10 mL) was stirred for 30 minutes at 0° C. It was dilutedwith water, extracted with DCM (×2). The organic layer was dried,concentrated to give desired compound as orange solid (331 mg, 100%)that was used without further purification. ESI-MS m/z: 278.1 [M+H]⁺.

Example 79 Step b

A solution of the isocyanate from step a (331 mg, 1.20 mmol),formylhydrazine (108 mg, 1.79 mmol) and DIPEA (1 mL) in DMF (5 mL) wasstirred for 2 hours. The reaction mixture was purified by reverse phaseC18 column chromatography (MeCN:H₂O) to give the desired compound as awhite solid (220 mg, 55%). ESI-MS m/z: 338.1 [M+H]⁺.

Example 79 Step c

A solution of the compound from step b (190 mg, 0.56 mmol), PPh₃ (443mg, 1.69 mmol), CCl₄ (0.4 mL), and TEA (0.5 mL) in MeCN (5 mL) wasstirred for 30 minutes. Water was added and the aqueous phase wasextracted with EtOAc (×2) and the organics were dried (Na₂SO₄),concentrated, and purified by prep-HPLC to give the title compound as ayellow solid (12 mg, 7%). ESI-MS m/z: 320.3 [M+H]⁺. ¹H NMR (300 MHz,DMSO-d₆) δ 5.08 (d, J=8.6 Hz, 1H), 7.18-7.78 (m, 9H), 8.57 (s, 1H), 8.94(d, J=8.6 Hz, 1H), 10.96 (s, 1H).

Example 80

Example 80 Step a

Example 80 was prepared using a procedure similar to that used toprepare Example 20 where 4-fluorobenzoic acid was used in place of5-chlorofuran-2-carboxylic acid. The title compound was also used toprepare Example 7.

Example 80 Step b

To a NMP solution (3 mL) of2-(4-fluorobenzoyl)-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)hydrazine-1-carbothioamide(447 mg, 1.0 mmol), prepared in step a, was added TEA (0.28 mL, 2.0mmol) and then TsCl (229 mg, 1.2 mmol). The mixture was stirred for 2 hat room temperature. DCM was added and the mixture was washed with waterand brine. The organic phase was dried (Na₂SO₄), concentrated andpurified by prep-HPLC to desired compound as light yellow solid (142 mg,33%). ESI-MS m/z: 430.1 [M+H]⁺. ¹H-NMR (300 MHz, DMSO-d₆) δ 5.37 (d,J=7.6 Hz, 1H), 7.23-7.39 (m, 5H), 7.44-7.55 (m, 5H), 7.68 (m, 1H), 7.82(dd, J=8.7, 5.5 Hz, 2H), 9.16 (d, J=7.7 Hz, 1H), 10.98 (s, 1H).

Example 81

Example 81 was prepared using a procedure similar to that used toprepare Example 80 where benzoic acid was used in place of4-fluorobenzoic acid. ESI-MS m/z: 412.3 [M+H]⁺. ¹H NMR (300 MHz,DMSO-d₆) δ 5.40 (d, J=7.6 Hz, 1H), 7.34 (dd, J=19.8, 7.9 Hz, 3H),7.42-7.64 (m, 8H), 7.63-7.74 (m, 1H), 7.73-7.94 (m, 2H), 9.16 (d, J=7.7Hz, 1H), 10.98 (s, 1H).

Example 82

Example 82 was prepared using a procedure similar to that used toprepare Example 80 where 4-cyanobenzoic acid was used in place of4-fluorobenzoic acid. ESI-MS m/z: 437.2 [M+H]⁺. ¹H NMR (300 MHz, CD₃OD:CDCl₃=2:1) δ 5.46 (s, 1H), 7.20-7.35 (m, 2H), 7.35-7.50 (m, 3H),7.50-7.60 (m, 3H), 7.60-7.70 (m, 1H), 7.75-7.95 (m, 2H), 7.95-8.10 (m,2H).

Example 83

Example 83 was prepared using a procedure similar to that used toprepare Example 80 where isonicotinic acid was used in place of4-fluorobenzoic acid. ESI-MS m/z: 413.1 [M+H]⁺. ¹H NMR (300 MHz,DMSO-d₆) δ 5.41 (d, J=7.4 Hz, 1H), 7.24-7.46 (m, 5H), 7.47-7.62 (m, 5H),7.63-7.79 (m, 3H), 8.63-8.72 (m, 2H), 9.42 (d, J=7.5 Hz, 1H), 11.03 (s,1H).

Example 84

Example 84 Step a

A solution of (Z)-3-amino-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one(251 mg, 1.0 mmol) in DCM (20 mL) was addeddi(1H-imidazol-1-yl)methanethione (178 mg, 1.0 mmol) at 0° C. The coldbat was removed and the reaction stirred at room temperature for 30minutes. Water was added to the mixture and it was extracted with EtOAc.The organic layer was washed with brine, dried (Na₂SO₄) and concentratedto afford the desired product as yellow foam (320 mg), which is useddirectly without any further purification. ESI-MS m/z: 294.2 [M+H]⁺.

Example 84 Step b

2-azido-1-phenylethanone (161 mg, 1.0 mmol) and PPh₃ (262 mg, 1.0 mmol)were added to the solution of compound from step a (293 mg, 1.0 mmol) indioxane (10 mL). The mixture was heated to 90° C. for 30 minutes underN₂. The reaction mixture was concentrated and the residue was purifiedby prep-HPLC to afford title product as white solid (20 mg, 5%). ESI-MSm/z: 395.1 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 5.19 (d, J=8.7 Hz, 1H),7.12-7.31 (m, 3H), 7.31-7.58 (m, 11H), 7.66 (m, 1H), 8.65 (d, J=8.7 Hz,1H), 10.83-11.08 (m, 1H).

Example 85

Example 85 Step a

A solution of (Z)-3-amino-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one(251 mg, 1.0 mmol) in DMF (5 mL) was addeddi(1H-imidazol-1-yl)methanethione (214 mg, 1.2 mmol) at 0° C. Afterstirring for 30 minutes, 2-amino-1-phenylethanone as the HCl salt (342mg, 2.0 mmol) and TEA (303 mg, 3.0 mmol) were added. The mixture wasstirred at room temperature for 30 minutes, then it was purified byreverse phase C18 column chromatography (MeCN:H₂O) to afford product asyellow solid (180 mg, 42%). ESI-MS m/z: 429.3 [M+H]⁺.

Example 85 Step b

A solution of the compound from step a (80 mg, 0.18 mmol) in 5 mL DCMwas added 50 mg H₂SO₄ (98%) at 0° C. After stirring for 30 minutes, itwas diluted with DCM and washed with water, dried (Na₂SO₄),concentrated, and purified by prep-HPLC to afford title product as whitesolid (35 mg, 46%). ESI-MS m/z: 411.2 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆)δ 5.37 (d, J=8.0 Hz, 1H), 7.10-7.59 (m, 14H), 7.66 (m, 1H), 8.94 (d,J=8.0 Hz, 1H), 10.90 (s, 1H).

Example 86

Example 86 Step a

A solution of (Z)-3-amino-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one(200 mg, 0.80 mmol), benzoyl isothiocyanate (0.11 mL, 0.80 mmol) in DCM(10 mL) was stirred for 2 hours at room temperature. The reactionmixture was concentrated and the resulting residue was purified bycolumn chromatography (silica, petroleum ether:EtOAc) to give thedesired compound as a yellow solid (390 mg, 100%). ESI-MS m/z: 415.2[M+H]⁺.

Example 86 Step b

A solution of the compound from step a (300 mg, 0.73 mmol) andNH₂NH₂.H₂O (0.1 mL) in EtOH (5 mL) was stirred for 3 hours at 60° C. Thereaction mixture was concentrated, diluted with water, extracted withEtOAc (×4), dried (Na₂SO₄), and concentrated. The crude product waspurified by prep-HPLC to give the title compound as a pink solid (30 mg,10%). ESI-MS m/z: 395.3 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 5.20 (d,J=8.8 Hz, 1H), 7.21-7.72 (m, 13H), 7.78-7.88 (m, 2H), 8.37 (s, 0.185H),10.94 (s, 1H).

Example 87

To a 20 mL vial was placed(Z)-3-amino-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one (141 mg, 0.56mmol), 5-chloro-3-phenyl-1,2,4-thiadiazole (100 mg, 0.51 mmol), and TEA(0.14 mL, 1.02 mmol) in DMF (2.5 mL) and the resulting mixture washeated to 70° C. overnight. The mixture was diluted with EtOAc, washedwith water and brine, dried (Na₂SO₄), concentrated, and purified viacolumn chromatography (silica, hexanes:EtOAc) to give the title compound(35 mg, 15%) as an off-white solid. ESI-MS m/z: 412.1 [M+H]⁺.

Example 88

Example 88 Step a

To a 20 mL vial was placed(Z)-3-amino-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one (324 mg, 1.29mmol), 3,5-dichloro-1,2,4-thiadiazole (200 mg, 1.29 mmol), and Et₃N(0.36 mL, 2.58 mmol) in DMF (5 mL) and the resulting mixture was heatedto 40° C. for 5 h. The mixture was diluted with EtOAc, washed with waterand brine, dried (Na₂SO₄), concentrated, and purified via columnchromatography (silica, hexanes:EtOAc) to give the title compound (190mg, 40%) as a yellow solid. ESI-MS m/z: 370.0 [M+H]⁺.

Example 88 Step b

To a 20 mL vial was placed the compound from step a (35 mg, 0.10 mmol)and morpholine (0.16 mL, 1.9 mmol) in dioxane (0.75 mL) and theresulting mixture was heated to 80° C. for 16 h. The mixture was dilutedwith EtOAc, washed with water and brine, dried (Na₂SO₄), concentrated,and purified via column chromatography (silica, hexanes:EtOAc) to givethe title compound (17 mg, 43%) as a yellow solid. ESI-MS m/z: 421.1[M+H]⁺.

Example 89

Example 89 was prepared using a procedure similar to that used toprepare Example 87 where 5-chloro-3-phenyl-1,2,4-oxadiazole was used inplace of 5-chloro-3-phenyl-1,2,4-thiadiazole. ESI-MS m/z: 396.1 [M+H]⁺.

Example 90

Example 90 Step a

Solid di(1H-imidazol-1-yl)methanethione (196 mg, 1.1 mmol) was added to(Z)-3-amino-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one (251 mg, 1.0mmol) in DMF (30 mL). The mixture was stirred for 1 h at roomtemperature. Solid NH₄Cl (1.6 g, 30 mmol) and TEA (5.1 g, 50 mmol) wereadded to the mixture and stirred for 3 h at room temperature. Thereaction mixture was poured into water, and extracted with EtOAc (×3).The organic layer was dried (Na₂SO₄) and concentrated to give crudeproduct as a brown solid (250 mg, 81%) that was used without furtherpurification. ESI-MS m/z: 311.0 [M+H]⁺.

Example 90 Step b

A solution of compound from step a (248 mg, 0.8 mmol) was added to2-bromo-1-phenylethanone (158 mg, 0.8 mmol) and AcOK (94 mg, 0.96 mmol)in EtOH (20 mL). The mixture was stirred for 1 h at 80° C., then it waspoured into water. The mixture was extracted with EtOAc (×3), and theorganic layer was dried (Na₂SO₄), concentrated, and the resultingresidue was purified by reverse phase C18 column chromatography(MeCN:H₂O) to give title compound as a light yellow solid (142 mg, 43%).ESI-MS m/z: 411.0 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 5.40 (d, J=7.7 Hz,1H), 7.10-7.60 (m, 12H), 7.63-7.75 (m, 3H), 8.74 (d, J=7.8 Hz, 1H),10.95 (s, 1H).

Example 91

Example 91 Step a

A solution of (Z)-benzyl2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-ylcarbamate (6.0g, 7.8 mmol; from Example 1 step c), PMBCl (3.7 g, 23.4 mmol) and K₂CO₃(4.3 g, 31.2 mmol) in DMF (100 mL) was heated to 50° C. overnight. Thesolution was poured into water and extracted with EtOAc. The organiclayer was dried (Na₂SO₄), concentrated, and it was purified by columnchromatography (silica, petroleum ether:EtOAc) to give the desiredproduct (5.0 g, 64%) as yellow solid. ESI-MS m/z: 506.4 [M+H]⁺.

Example 91 Step b

A solution of the compound from step a (5.8 g, 11.5 mmol) in 48%HBr/AcOH (50 mL) was heated to 70° C. for 30 minutes. Ether was added tothe solution and the resulting solid was collected by filtration. Thecollected solid was added to the saturated NaHCO₃, and was extractedwith EtOAc. The organic layer was dried (Na₂SO₄), concentrated and theresidue was purified by column chromatography (silica, DCM:MeOH) to give3-amino-1-(4-methoxybenzyl)-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one(2.4 g, 56%) as yellow foam. ESI-MS m/z: 372.2 [M+H]⁺.

Example 91 Step c

A solution of(Z)-3-amino-1-(4-methoxybenzyl)-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one,from step b, (185 mg, 0.5 mmol) and benzoyl isothiocyanate (82 mg, 0.5mmol) in DCM (20 mL) was stirred at room temperature for 2 h. Thereaction mixture was concentrated and purified by reverse phase C18column chromatography (MeCN:H₂O) to obtain desired product as yellowsolid (155 mg, 58%). ESI-MS m/z: 535.3 [M+H]⁺.

Example 91 Step d

Solid NaH (15 mg, 0.58 mmol) was added to the compound from step c (155mg, 0.29 mmol) in THF (20 ml) at 0° C. After stirring for 30 minutes,neat MeI (82 mg, 0.58 mmol) was added. The mixture was stirred at roomtemperature for 3 h. The solvent was removed and the residue was useddirectly in the next step. ESI-MS m/z: 549.3 [M+H]⁺.

Example 91 Step e

The crude compound from step d was dissolved in ethanol (5 mL).Hydroxylamine hydrochloride (40 mg, 0.58 mmol) was added and the mixturewas heated at 75° C. for 3 h. The resulting mixture was concentratedunder vacuum and water was added. The resulting precipitate was filteredoff to give the desired compound (100 mg, 67%) as a light yellow solid.ESI-MS m/z: 516.4 [M+H]⁺.

Example 91 Step f

To the compound from step e (100 mg, 0.19 mmol) in MeCN (10 mL) andwater (10 mL) was added CAN (153 mg, 0.28 mmol). The resulting solutionwas stirred at room temperature for 4 h. The solution was diluted with20 mL of EtOAc, washed with water, dried (Na₂SO₄), concentrated andpurified by prep-HPLC to obtain the title product as a white solid (27mg, 19%). ESI-MS m/z: 396.3 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆): δ 5.06(d, J=8.7 Hz, 1H), 7.20-7.80 (m, 12H), 7.93-8.14 (m, 3H), 10.96 (s, 1H).

Example 92

Example 92 Step a

To a solution of Z)-3-amino-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one(1.0 g, 4.0 mmol) in ^(i)PrOH (60 mL) was added to4,6-dichloropyrimidine (1.2 g, 2.0 mmol) and DIPEA (1.3 g, 2.5 mmol).The mixture was stirred for 18 h at 90° C. The reaction was concentratedand the residue was triturated with Et₂O (20 mL) and H₂O (3 mL), anddried under vacuum to give desired compound as a white solid (800 mg,55%). ESI-MS m/z: 364.2 [M+H]⁺.

Example 92 Step b

To a solution of compound from step a (109 mg, 0.30 mmol) in dioxane (4mL) and H₂O (1 mL) was added to phenylboronic acid (73.2 mg, 0.60 mmol),Pd(dtbpf)Cl₂ (20 mg, 0.03 mmol) and KF (174 mg, 3.0 mmol). The mixturewas heated to 100° C. in the microwave for 1 h. The reaction mixture waspurified directly by reverse phase C18 column chromatography (MeCN:H₂O)to give desired compound as a white solid (22 mg, 18%). ESI-MS m/z:406.1 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 5.65 (d, J=7.6 Hz, 1H),7.23-7.61 (m, 12H), 7.68 (m, 1H), 7.96-8.11 (m, 2H), 8.47 (d, J=1.1 Hz,1H), 8.57 (s, 1H), 10.90-10.97 (m, 1H).

Example 93

To a solution of the compound from Example 92 step a (182 mg, 0.5 mmol)in DMF (5 mL) was added K₂CO₃ (138 mg, 1.0 mmol) and morpholine (2 mL).The mixture was heated to 140° C. for 1h in the microwave, then it waspoured into water and extracted with EtOAc (×3). The organic layer wasdried (Na₂SO₄), concentrated, and purified by reverse phase C18 columnchromatography (MeCN:H₂O) to give the title compound as white solid (63mg, 30%). ESI-MS m/z: 415.1 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 3.43 (m,4H), 3.68 (dd, J=5.8, 3.9 Hz, 4H), 5.59 (d, J=8.1 Hz, 1H), 6.05-6.12 (m,1H), 7.20-7.60 (m, 8H), 7.66 (m, 1H), 7.78 (s, 1H), 7.97 (s, 1H), 10.86(s, 1H).

Example 94

To a solution of the compound from Example 92 step a (182 mg, 0.5 mmol)in DMF (6 mL) was added K₂CO₃ (414 mg, 3.0 mmol) and phenol (282 mg, 3.0mmol). The mixture was heated for 3 h at 130° C. in the microwave. Thereaction mixture was purified directly by reverse phase C18 columnchromatography (MeCN:H₂O) to give desired compound as a white solid (20mg, 10%). ESI-MS m/z: 415.1 [M+H]⁺. 1H NMR (300 MHz, DMSO-d₆) δ 5.56 (s,1H), 6.26 (s, 1H), 7.10-7.37 (m, 6H), 7.37-7.57 (m, 7H), 7.64 (m, 1H),8.07 (s, 1H), 8.52 (s, 1H), 10.86 (s, 1H).

Example 95

Example 95 Step a

A solution of3-amino-1-(4-methoxybenzyl)-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one,from Example 91 step b, (500 mg, 1.35 mmol), 3-chloro-6-phenylpyridazine(257 mg, 1.35 mmol), Brettphos (72 mg, 0.14 mmol) and K₂CO₃ (372 mg,2.70 mmol) in t-BuOH (5 mL) were stirred under nitrogen for 30 minutesat room temperature before 3rd Generation Brettphos precatalyst (122 mg,0.14 mmol) was added. The reaction was stirred for 12 hours at 90° C.The mixture was diluted with EtOAc, washed with water (×2), dried(Na₂SO₄), concentrated and purified by reverse phase C18 columnchromatography (MeCN:H₂O) to give desired compound as light yellow solid(100 mg, 14%). ESI-MS m/z: 526.4 [M+H]⁺.

Example 95 Step b

To a solution of the compound from step a (87 mg, 0.17 mmol) in anisole(5 mL) was added AlCl₃ (220 mg, 1.65 mmol) and the mixture was stirredfor 3 hours at 70° C. The reaction mixture was purified directly byprep-HPLC to give the title compound as a white solid (31 mg, 47%).ESI-MS m/z: 406.3 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) 5.69 (d, J=7.7 Hz,1H), 7.25-7.70 (m, 13H), 7.91-7.98 (m, 3H), 8.12 (d, J=7.7 Hz, 1H),10.92 (s, 1H).

Example 96

Example 96 Step a

A solution of Z)-3-amino-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one(500 mg, 2.0 mmol), 2,4-dichloropyrimidine (600 mg, 4.0 mmol), DIEA (1.5ml, 9.0 mmol) in ^(i)PrOH (60 mL) were heated to 90° C. overnight. Thereaction mixture was cooled to room temperature, diluted with DCM, andwashed with water (×2). The organic layer was dried (Na₂SO₄),concentrated, and purified by reverse phase C18 column chromatography(MeCN:H₂O) to give desired compound as a beige solid (530 mg, 41%).ESI-MS m/z: 364.1 [M+H]⁺.

Example 96 Step b

A solution of the compound from step a (200 mg, 0.55 mmol),phenylboronic acid (300 mg, 2.46 mmol), Pd(dtbpf)Cl₂ (80 mg, 0.06 mmol),KF (500 mg, 8.2 mmol), in H₂O (1 mL) and 1.4-dioxane (5 mL) was heatedto 100° C. in the microwave for 1.5 hours. The reaction mixture waspurified by prep-HPLC to give the title compound as a white solid (26mg, 11%). ESI-MS m/z: 406.2 [M+H]⁺. ¹H NMR (300 MHz, Methanol-d₄) δ 5.80(s, 1H), 6.79 (s, 1H), 7.28-7.58 (m, 21H), 7.70 (ddd, J=8.4, 7.2, 1.6Hz, 2H), 8.11 (d, J=7.6 Hz, 3H), 8.25 (d, J=6.1 Hz, 2H).

Example 97

Example 97 Step a

A solution of 3-bromo-2-hydroxypyridine (2.0 g, 12 mmol), benzyl bromide(1.9 g, 12 mmol), and K₂CO₃ (4.9 g, 36 mmol) in DMF (100 mL) was stirredfor 3 hour at rt. The reaction mixture was diluted with water andextracted with EtOAc (×3). The organic layer was dried (Na₂SO₄),concentrated, and purified by column chromatography (silica, petroleumether:EtOAc) to give desired compound as yellow oil (3 g, 95%). ESI-MSm/z: 264.1 [M+H]⁺.

Example 97 Step b

A solution of the compound from step a (87 mg, 0.33 mmol),Z)-3-amino-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one (100 mg, 0.40mmol), Pd(OAc)₂ (11 mg, 0.05 mmol), and CsCO₃ (220 mg, 0.66 mmol) in DMF(5 mL) was stirred for 5 h at 120° C. The mixture was purified directlyby prep-HPLC to give the title compound as a white solid (5 mg, 4%).ESI-MS m/z: 435.3 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 11.08 (s, 1H),8.48 (s, 1H), 7.64 (m, 1H), 7.56-7.21 (m, 14H), 7.12 (dd, J=5.9, 2.6 Hz,1H), 6.58 (d, J=6.9 Hz, 1H), 6.20-6.07 (m, 2H), 5.17 (s, 2H), 4.91 (d,J=6.9 Hz, 1H).

Example 98

To a solution of Z)-3-amino-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one(502 mg, 2.0 mmol) in ^(i)PrOH (20 mL) was added 2-chloroquinazoline(164 mg, 1.0 mmol) and TsOH (1.0 mmol). The mixture was stirred for 24 hat 80° C. The reaction mixture was concentrated and purified byprep-HPLC to give desired compound as white solid (17 mg, 4%). ESI-MSm/z: 445.1 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 5.63 (d, J=7.9 Hz, 1H),7.24-7.59 (m, 10H), 7.59-7.80 (m, 3H), 7.87 (d, J=8.0 Hz, 1H), 8.48 (s,1H), 9.23 (s, 1H), 10.92 (s, 1H).

Example 99

To a solution of Z)-3-amino-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one(502 mg, 2.0 mmol) in DMF (8 mL) was added 2,6-dichlorobenzo[d]oxazole(449 mg, 2.4 mmol) and TEA (404 mg, 2 mmol). The mixture was stirred at60° C. for 1 h, then poured into water. The mixture was extracted withEtOAc (×3), the organic layer was dried (Na₂SO₄) and concentrated. Theresidue was purified by prep-HPLC to give desired compound as whitesolid (500 mg, 62%). ESI-MS m/z: 403.2 [M+H]⁺. 1H NMR (300 MHz, DMSO-d₆)δ 5.31 (d, J=8.3 Hz, 1H), 7.12-7.76 (m, 12H), 9.50 (d, J=8.3 Hz, 1H),10.98 (s, 1H).

Example 100

Example 100 was prepared using a procedure similar to that used toprepare Example 99 where 2-chlorobenzo[d]oxazole was used in place of2,6-dichlorobenzo[d]oxazole. ESI-MS m/z: 369.1 [M+H]⁺.

Example 101

To a solution of Z)-3-amino-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one(50 mg, 0.2 mmol) in DMSO (1 mL) was added to1-iodo-2-isothiocyanatobenzene (46 mg, 0.3 mmol), ^(n)Bu₄NBr (91 mg, 0.3mmol), and CuBr (7 mg, 0.05 mmol) and the resulting mixture was stirredat 60° C. for 2 h. The reaction mixture was purified by prep-HPLC togive desired compound as light yellow solid (12 mg, 17%). ESI-MS m/z:385.2 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 5.52 (d, J=7.9 Hz, 1H), 7.05(m, 1H), 7.14-7.61 (m, 10H), 7.64-7.77 (m, 2H), 9.26 (d, J=7.9 Hz, 1H),10.96 (s, 1H).

Example 102

Example 102 Step a

To a 100 mL round-bottomed flask were added5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one (1.05 g, 4.4 mmol)and DMF (40 mL) and cooled to 0° C. The reaction mixture was treatedwith NaH 60% in oil (213 mg, 5.3 mmol), stirred for 20 min., allowed towarm to room temperature, treated with PMB-Cl (0.72 mL, 5.3 mmol) andstirred for 3.5 hrs. The reaction was cooled to 0° C., quenched byaddition of sat. NH₄Cl sol'n (10 mL), diluted with ethyl acetate-MTBE(100 mL) and filtered. The filtrate was washed with H₂O (3×30 mL) andbrine. Dried over Na₂SO₄, filtered and evaporated to dryness. Theresidue was purified by column chromatography (silica, hexanes:EtOAc) togive the title compound (1.262 g) as a colorless solid. ESI MSm/z=357.16 [M+H]⁺.

Example 102 Step b

To a 25 mL round-bottomed flask were added the compound from step a(0.569 g, 1.0 equiv., 1.6 mmol) and THF (8 mL) and cooled to −65° C. Thereaction mixture was treated with t-BuOK (1.68 mL, 1M in THF, 1.7 mmol)and stirred for 30 min. Methyl iodide (0.109 mL, 1.8 mmol) in THF (2 mL)was added to the reaction via cannular, slowly allowed to warm to 2° C.for 1.5 hour and stirred at room temperature for 15 min. The reactionwas cooled to 0° C., quenched by addition of sat. NH₄Cl sol'n (2 mL),diluted with ethyl acetate, washed with H₂O and brine. Dried overNa₂SO₄, filtered and evaporated to dryness. The residue was purified bycolumn chromatography (silica, hexanes:acetone) to give the titlecompound (519.6 mg) as a colorless solid. ESI MS m/z=371.17 [M+H]⁺.

Example 102 Step c

To a 25 mL round-bottomed flask were added the compound from step b (0.1g, 1.0 equiv., 0.27 mmol), DME (6 mL)-THF (1 mL), HMPA (0.28 mL, 1.62mmol) and cooled to −40° C. The reaction mixture was treated with KHMDS(mL, 0.5M in toluene, 1.08 mmol) and stirred for 100 min. Then, trisylazide (570 mg, 1.84 mmol) in THF (1.5 mL) was added to the reaction viacannular and stirred for 2 hours. The reaction mixture was treated withAcOH (0.28 mL, 4.86 mmol) and slowly allowed to warm to room temperaturefor 100 min. Then, the reaction was diluted with ethyl acetate, washedwith sat. NaHCO₃sol'n, H₂O and brine. Dried over Na₂SO₄, filtered andevaporated to dryness. The residue was purified by column chromatography(silica, hexanes:acetone) to give the title compound as a colorlesssolid (˜60% purity). ESI MS m/z=412.17 [M+H]⁺.

Example 102 Step d

To a mixture of the compound from step c (62 mg, ˜60% purity) and H₂O (1drop) in THF (0.9 mL) was added PPh₃ (200 mg, 0.76 mmol), heated at 60°C. for 2 hours and evaporated to dryness. The residue was purified bycolumn chromatography (silica, DCM:MeOH) to give the title compound (14mg) as a colorless solid. ESI MS m/z=386.19 [M+H]⁺.

Example 103

Example 103 was prepared using a procedure similar to that used toprepare Example 99 where 2-chloro-6-fluorobenzo[d]oxazole was used inplace of 2,6-dichlorobenzo[d]oxazole. ESI-MS m/z: 387.1 [M+H]⁺.

Example 104

Example 104 was prepared using a procedure similar to that used toprepare Example 99 where 2-chloro-5-fluorobenzo[d]oxazole was used inplace of 2,6-dichlorobenzo[d]oxazole. ESI-MS m/z: 387.1 [M+H]⁺.

Example 105

Example 105 was prepared using a procedure similar to that used toprepare Example 99 where 2-chloro-4-fluorobenzo[d]oxazole was used inplace of 2,6-dichlorobenzo[d]oxazole. ESI-MS m/z: 387.1 [M+H]⁺.

Example 106

Example 106 was prepared using a procedure similar to that used toprepare Example 99 where 2-chloro-5-methylbenzo[d]oxazole was used inplace of 2,6-dichlorobenzo[d]oxazole. ESI-MS m/z: 383.1 [M+H]⁺.

Example 107

Example 107 was prepared using a procedure similar to that used toprepare Example 20 where 5-(methylsulfonyl)picolinic acid was used inplace of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 475.3 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 3.41 (s, 3H), 5.23 (d, J=6.3 Hz, 1H), 7.26-7.42(m, 2H), 7.43-7.59 (m, 6H), 7.70 (td, J=7.7, 7.0, 1.8 Hz, 1H), 8.25 (d,J=8.4 Hz, 1H), 8.49 (dd, J=8.4, 2.4 Hz, 1H), 9.19 (d, J=2.1 Hz, 1H),9.59 (s, 1H), 11.04 (s, 1H).

Example 108

Example 108 was prepared using a procedure similar to that used toprepare Example 20 where 5-(dimethylamino)picolinic acid was used inplace of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 440.3 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 3.02 (s, 6H), 5.14 (d, J=8.6 Hz, 1H), 7.18 (m,1H), 7.23-7.39 (m, 3H), 7.42-7.57 (m, 5H), 7.62-7.79 (m, 2H), 8.16 (d,J=3.0 Hz, 1H), 9.03 (d, J=8.7 Hz, 1H), 10.98 (s, 1H).

Example 109

Example 109 was prepared using a procedure similar to that used toprepare Example 20 where 6-chloro-5-methoxypicolinic acid was used inplace of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 461.3 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 3.97 (s, 3H), 5.16 (d, J=8.5 Hz, 1H), 7.22-7.40(m, 3H), 7.42-7.57 (m, 5H), 7.61-7.79 (m, 2H), 7.98 (d, J=8.5 Hz, 1H),9.27 (d, J=8.5 Hz, 1H), 10.99 (s, 1H).

Example 110

Example 110 was prepared using a procedure similar to that used toprepare Example 20 where 5-fluoro-6-methylpicolinic acid was used inplace of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 429.2 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 2.50 (s, 3H), 5.17 (d, J=8.5 Hz, 1H), 7.22-7.41(m, 3H), 7.42-7.59 (m, 5H), 7.67 (ddd, J=8.4, 7.0, 1.8 Hz, 1H), 7.81 (t,J=8.9 Hz, 1H), 7.89 (dd, J=8.6, 3.9 Hz, 1H), 9.28 (d, J=8.5 Hz, 1H),10.99 (s, 1H).

Example 111

Example 111 was prepared using a procedure similar to that used toprepare Example 20 where 3-morpholinobenzoic acid was used in place of5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 481.2 [M+H]⁺. 1H NMR (300MHz, DMSO-d₆) δ 3.15 (t, J=4.9 Hz, 4H), 3.75 (dd, J=6.0, 3.6 Hz, 4H),5.10-5.19 (m, 1H), 7.08-7.73 (m, 14H), 7.82 (s, 1H), 8.99-9.09 (m, 1H),10.99 (s, 1H).

Example 112

Example 112 was prepared using a procedure similar to that used toprepare Example 20 where 3-fluoro-4-morpholinobenzoic acid was used inplace of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 499.4 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 3.11 (t, J=4.7 Hz, 4H), 3.75 (dd, J=6.0, 3.3Hz, 4H), 5.10-5.17 (m, 1H), 7.12-7.40 (m, 4H), 7.41-7.73 (m, 8H), 9.07(d, J=7.8 Hz, 1H), 11.00 (s, 1H).

Example 113

Example 113 was prepared using a procedure similar to that used toprepare Example 20 where 3-methyl-4-morpholinobenzoic acid was used inplace of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 440.3 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 2.33 (s, 3H), 2.81-2.99 (m, 4H), 3.71-3.84 (m,4H), 5.15 (d, J=8.6 Hz, 1H), 7.16 (d, J=8.3 Hz, 1H), 7.25-7.39 (m, 3H),7.43-7.57 (m, 5H), 7.59-7.73 (m, 3H), 9.03 (d, J=8.6 Hz, 1H), 10.99 (s,1H).

Example 114

Example 114 was prepared using a procedure similar to that used toprepare Example 20 where 5-morpholinopicolinic acid was used in place of5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 482.2 [M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 3.31 (m, 4H), 3.77 (m, 4H), 5.17 (d, J=8.3 Hz, 1H),7.21-7.87 (m, 11H), 8.41 (d, J=2.9 Hz, 1H), 9.13 (d, J=8.4 Hz, 1H),11.01 (s, 1H).

Example 115

Example 115 was prepared using a procedure similar to that used toprepare Example 20 where 6-morpholinonicotinic acid was used in place of5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 482.4[M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 3.52-3.60 (m, 4H), 3.70 (dd, J=5.8, 3.8 Hz, 4H), 5.13(d, J=8.5 Hz, 1H), 6.98 (d, J=9.1 Hz, 1H), 7.22-7.38 (m, 3H), 7.41-7.57(m, 5H), 7.66 (ddd, J=8.5, 7.0, 1.7 Hz, 1H), 7.90 (dd, J=9.0, 2.4 Hz,1H), 8.44-8.58 (m, 1H), 8.98 (d, J=8.6 Hz, 1H), 10.98 (s, 1H).

Example 116

Example 116 was prepared using a procedure similar to that used toprepare Example 20 where 4-(cyclohexylamino)benzoic acid was used inplace of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 493.4[M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 1.48-1.05 (m, 5H), 1.60 (d, J=12.5 Hz, 1H),1.84-1.65 (m, 2H), 1.92 (d, J=12.0 Hz, 2H), 3.20 (m, 1H), 5.11 (d, J=8.7Hz, 1H), 6.14 (d, J=7.8 Hz, 1H), 6.72-6.50 (m, 2H), 7.38-7.22 (m, 3H),7.56-7.41 (m, 7H), 7.66 (m, 1H), 8.79 (d, J=8.8 Hz, 1H), 10.95 (s, 1H).

Example 117

Example 117 was prepared using a procedure similar to that used toprepare Example 20 where 4-((2-methoxyethyl)amino)benzoic acid was usedin place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 469.0 [M+H]⁺.¹H NMR (300 MHz, DMSO-d₆) δ 3.27 (d, J=6.8 Hz, 5H), 3.49 (t, J=5.6 Hz,2H), 5.11 (d, J=8.7 Hz, 1H), 6.34 (t, J=5.6 Hz, 1H), 6.75-6.60 (m, 1H),7.40-7.20 (m, 3H), 7.58-7.40 (m, 7H), 7.66 (ddd, J=8.6, 7.0, 1.7 Hz,1H), 8.83 (d, J=8.8 Hz, 1H), 10.98 (s, 1H).

Example 118

Example 118 was prepared using a procedure similar to that used toprepare Example 20 where 4-((2-methoxyethyl)(methyl)amino)benzoic acidwas used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 483.4[M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 2.98 (s, 3H), 3.25 (s, 3H),3.64-3.43 (m, 4H), 5.12 (d, J=8.7 Hz, 1H), 6.89-6.63 (m, 2H), 7.39-7.20(m, 3H), 7.56-7.39 (m, 5H), 7.72-7.55 (m, 3H), 8.86 (d, J=8.7 Hz, 1H),10.97 (s, 1H).

Example 119

Example 119 was prepared using a procedure similar to that used toprepare Example 20 where 5-fluoro-2-morpholinobenzoic acid was used inplace of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 499.0 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 2.75-2.97 (m, 4H), 3.56-3.84 (m, 4H), 5.17 (d,J=8.6 Hz, 1H), 7.19-7.41 (m, 5H), 7.42-7.57 (m, 6H), 7.67 (ddd, J=8.4,7.0, 1.7 Hz, 1H), 9.17 (d, J=8.6 Hz, 1H), 10.99 (s, 1H).

Example 120

Example 120 was prepared using a procedure similar to that used toprepare Example 20 where 2-morpholinonicotinic acid was used in place of5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 482.3 [M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 3.07-3.20 (m, 4H), 3.68 (m, 4H), 5.15 (d, J=8.6 Hz, 1H),7.04 (dd, J=7.6, 4.8 Hz, 1H), 7.24-7.38 (m, 3H), 7.41-7.60 (m, 5H), 7.67(ddd, J=8.5, 7.1, 1.8 Hz, 1H), 7.96 (dd, J=7.6, 1.9 Hz, 1H), 8.35 (dd,J=4.8, 1.9 Hz, 1H), 9.16 (d, J=8.6 Hz, 1H), 10.98 (s, 1H).

Example 121

Example 121 was prepared using a procedure similar to that used toprepare Example 20 where 4-(methylsulfonyl)-2-morpholinobenzoic acid wasused in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 559.4[M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 2.86-3.07 (m, 4H), 3.27 (s, 3H),3.72 (t, J=4.7 Hz, 4H), 5.18 (d, J=8.3 Hz, 1H), 7.24-7.39 (m, 3H),7.42-7.71 (m, 8H), 7.92 (d, J=8.1 Hz, 1H), 9.31 (d, J=8.5 Hz, 1H), 11.00(s, 1H).

Example 122

Example 122 was prepared using a procedure similar to that used toprepare Example 20 where 2-chloro-4-morpholinobenzoic acid was used inplace of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 515.5 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 3.72 (t, J=4.8 Hz, 4H), 5.14 (d, J=8.5 Hz, 1H),6.99-7.16 (m, 2H), 7.19-7.60 (m, 8H), 7.58-7.79 (m, 2H), 9.01 (d, J=8.5Hz, 1H), 10.98 (s, 1H).

Example 123

Example 123 was prepared using a procedure similar to that used toprepare Example 20 where 2-morpholino-4-(trifluoromethyl)benzoic acidwas used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 549.2[M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 2.97 (s, 3H), 5.18 (d, J=8.3 Hz,1H), 7.13-7.82 (m, 11H), 8.22 (d, J=1.9 Hz, 1H), 9.47 (d, J=8.4 Hz, 1H),11.00 (s, 1H).

Example 124

Example 124 was prepared using a procedure similar to that used toprepare Example 20 where 4-morpholinobenzoic acid was used in place of5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 481.2 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 3.22-3.24 (m, 4H), 3.73-3.75 (m, 4H), 5.12-5.14 (d,J=8.0 Hz, 1H), 7.06-7.08 (m, 2H), 7.26-7.29 (m, 1H), 7.33-7.36 (m, 2H),7.44-7.49 (m, 5H), 7.51-7.77 (m, 1H), 8.93-8.95 (d, J=8.0 Hz, 1H) 10.98(s, 1H).

Example 124a

Example 124a was separated from racemic Example 7 using a ChiralpakIC2*25 cm, SumChiral-P(IC)004S90IC0SCJ-QF001 column. ESI-MS m/z: 481.2[M+H]⁺.

Example 124b

Example 124b was separated from racemic Example 7 using a ChiralpakIC2*25 cm, SumChiral-P(IC)004S90IC0SCJ-QF001 column. ESI-MS m/z: 481.2[M+H]⁺.

Example 125

Example 125 was prepared using a procedure similar to that used toprepare Example 20 where 2-morpholinobenzoic acid was used in place of5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 481.3 [M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 2.90 (dd, J=5.7, 3.4 Hz, 4H), 3.71 (t, J=4.6 Hz, 4H),5.18 (d, J=8.7 Hz, 1H), 7.08-7.24 (m, 2H), 7.24-7.42 (m, 3H), 7.42-7.61(m, 6H), 7.61-7.83 (m, 2H), 9.10 (d, J=8.8 Hz, 1H), 10.99 (s, 1H).

Example 125a

Example 125a was separated from racemic Example 7 using a ChiralpakIC2*25 cm, 5 um Chiral-P(IC)004S90IC0SCJ-QF001 column. ESI-MS m/z: 481.3[M+H]⁺.

Example 125b

Example 125b was separated from racemic Example 7 using a ChiralpakIC2*25 cm, SumChiral-P(IC)004S90IC0SCJ-QF001 column. ESI-MS m/z: 481.3[M+H]⁺.

Example 126

Example 126 was prepared using a procedure similar to that used toprepare Example 20 where 2-fluoro-4-morpholinobenzoic acid was used inplace of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 499.4 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 2.90 (t, J=4.5 Hz, 4H), 3.69 (td, J=4.2, 2.0Hz, 4H), 5.16 (d, J=8.7 Hz, 1H), 6.92-7.03 (m, 2H), 7.24-7.39 (m, 3H),7.42-7.59 (m, 5H), 7.63-7.74 (m, 2H), 9.11 (d, J=8.7 Hz, 1H), 10.98 (s,1H).

Example 126a

Example 126a was separated from racemic Example 7 using a Chiralpak IB-3100*3 mm, 3 μm, column. ESI-MS m/z: 499.2 [M+H]⁺.

Example 126b

Example 126b was separated from racemic Example 7 using a Chiralpak IB-3100*3 mm, 3 μm, column. ESI-MS m/z: 499.2 [M+H]⁺.

Example 127

Example 127 Step a

A solution of compound 2-chloro-4-fluorobenzoic acid (5.2 g, 30 mmol),CuI (570 mg, 3 mmol), K₂CO₃ (1.8 g, 90 mmol) and morpholine (10 mL) inDMF (100 mL) was stirred for 2 hours at 90° C. The mixture wasconcentrated and purified by reverse phase C18 column chromatography(MeCN:H₂O) to give 4-fluoro-2-morpholinobenzoic acid as a white solid(900 mg, 13%). ESI-MS m/z: 226.0 [M+H]⁺.

Example 127 Step b

Example 127 was prepared using a procedure similar to that used toprepare Example 20 where 4-fluoro-2-morpholinobenzoic acid was used inplace of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 499.2 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 2.92 (d, J=4.6 Hz, 4H), 3.71 (m, 4H), 5.17 (d,J=8.7 Hz, 1H), 6.91-7.06 (m, 2H), 7.23-7.41 (m, 3H), 7.42-7.62 (m, 5H),7.63-7.77 (m, 2H), 9.13 (d, J=8.8 Hz, 1H), 11.00 (s, 1H).

Example 128

Example 128 Step a

A solution of the 2-chloro-4-(1H-1, 2, 4-triazol-1-yl) benzoic acid (300mg, 1.34 mmol) in morpholine (5 mL) was stirred at 120° C. for 2 hours.Water (20 mL) was added to the mixture and it was extracted with EtOAc(×3). The organic layer was dried and purified by by reverse phase C18column chromatography to give 2-chloro-4-(1H-1,2,4-triazol-1-yl)benzoicacid as off-white solid (200 mg, 54%). ESI-MS m/z: 275.1 [M+H]⁺.

Example 128 Step b

Example 128 was prepared using a procedure similar to that used toprepare Example 20 where 2-chloro-4-(1H-1,2,4-triazol-1-yl)benzoic acidwas used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 548.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 2.97-2.99 (m, 4H), 3.74 (s, 4H),5.16-5.18 (d, J=8.0 Hz, 1H), 7.26-7.28 (m, 1H), 7.30-7.34 (m, 2H),7.36-7.48 (m, 5H), 7.51-7.53 (m, 3H), 7.54-7.60 (m, 1H), 8.29 (s, 1H),9.17-9.19 (m, 1H), 9.44 (s, 1H) 10.99 (s, 1H).

Example 129

Example 129 was prepared using a procedure similar to that used toprepare Example 20 where 2-morpholino-4-(1H-pyrazol-1-yl)benzoic acid,which was prepared similarly to2-chloro-4-(1H-1,2,4-triazol-1-yl)benzoic acid from Example 128 step a,was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 547.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 2.96-2.98 (m, 4H), 3.73 (s, 4H),5.16-5.18 (d, J=8.0 Hz, 1H), 6.59-6.60 (m, 1H), 7.26-7.36 (m, 2H),7.44-7.48 (m, 2H), 7.51-7.54 (m, 6H), 7.58-7.59 (m, 2H), 7.60-7.69 (m,1H), 7.77-7.80 (m, 2H), 8.64 (s, 1H), 9.12-9.14 (m, 1H), 9.44 (s, 1H)10.99 (s, 1H).

Example 130

Example 130 was prepared using a procedure similar to that used toprepare Example 20 where 2-morpholino-6-(trifluoromethyl)nicotinic acid,which was prepared similarly to2-chloro-4-(1H-1,2,4-triazol-1-yl)benzoic acid from Example 128 step a,was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 550.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 3.18-3.22 (m, 4H), 3.66-3.72 (m,4H), 5.16-5.18 (d, J=8.0 Hz, 1H), 7.26-7.28 (m, 1H), 7.30-7.34 (m, 2H),7.36-7.48 (m, 6H), 7.50-7.70 (m, 1H), 8.18-8.20 (m, 1H), 9.33-9.35 (d,J=8.0 Hz, 1H), 11.01 (s, 1H).

Example 131

Example 131 was prepared using a procedure similar to that used toprepare Example 20 where 4-cyano-2-morpholinobenzoic acid, which wasprepared similarly to 2-chloro-4-(1H-1,2,4-triazol-1-yl)benzoic acidfrom Example 128 step a, was used in place of 5-chlorofuran-2-carboxylicacid. ESI-MS m/z: 506.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 2.92-2.94(m, 4H), 3.71-3.75 (m, 4H), 5.17-5.19 (d, J=8.0 Hz, 1H), 7.26-7.28 (m,1H), 7.30-7.34 (m, 2H), 7.35-7.48 (m, 7H), 7.50-7.59 (m, 1H), 7.65-7.69(m, 1H), 9.29-9.31 (d, J=8.0 Hz, 1H), 10.99 (s, 1H).

Example 132

Example 132 Step a

A solution of 3-chloropicolinic acid (1 g, 6.37 mmol) and H₂SO₄ (1 mL)in EtOH (20 mL) was refluxed for 3 hours. It was concentrated andpurified by reverse phase C18 column chromatography (MeCN/H₂O) to giveethyl 3-chloropicolinate as a yellow oil (0.85 g, 72%). ESI-MS m/z:186.0 [M+H]⁺.

Example 132 Step b

A solution of ethyl 3-chloropicolinate (400 mg, 2.16 mmol) in morpholine(neat) (2 ml) was stirred overnight at 120° C. It was concentrated undervacuum and the crude product was purified by prep-TLC (PE/EtOAc=2/1) togive ethyl 3-morpholinopicolinate a yellow solid (0.17 g, 35%). ESI-MSm/z: 237.1 [M+H]⁺.

Example 132 Step c

A solution of ethyl 3-morpholinopicolinate (0.17 g, 0.72 mmol) andNH₂NH₂.H₂O (1 mL) in EtOH (10 mL) was refluxed overnight. The crudeproduct was purified by reverse phase C18 column chromatography(MeCN/H₂O) to give 3-morpholinopicolinohydrazide as a yellow oil (0.11g, 80%). ESI-MS m/z: 223.1 [M+H]⁺.

Example 132 Step d

Example 132 was prepared using a procedure similar to that used toprepare Example 21 where 3-morpholinopicolinohydrazide was used in placeof tetrahydro-2H-pyran-4-carbohydrazide. ESI-MS m/z: 482.5 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 2.87-3.08 (m, 4H), 3.71 (dd, J=5.7, 3.2 Hz,4H), 5.20 (d, J=8.5 Hz, 1H), 7.24-7.42 (m, 3H), 7.43-7.61 (m, 6H),7.62-7.75 (m, 2H), 8.35 (dd, J=4.5, 1.3 Hz, 1H), 9.21 (d, J=8.6 Hz, 1H),11.00 (s, 1H).

Example 133

Example 133 Step a

A solution of 4-chloronicotinic acid (1.00 g, 6.0 mmol), morpholine(1.26 g, 14.0 mmol) and K₂CO₃ (1.33 g, 9.6 mmol) in DMSO (5 mL) wasstirred for 12 hours at 120° C. It was diluted with EtOH, the solid wasfiltered out. The filtrate was concentrated, and it was precipitated byadding MeCN (20 mL) to give 1.06 g (71%) as white solid. ESI-MS m/z:208.9 [M+H]⁺.

Example 133 Step b

Example 133 was prepared using a procedure similar to that used toprepare Example 20 where potassium 4-morpholinonicotinate was used inplace of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 482.3 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 3.03 (s, 4H), 3.69 (s, 4H), 5.15 (d, J=8.7 Hz,1H), 7.03 (d, J=5.7 Hz, 1H), 7.29 (m, 1H), 7.35 (m, 2H), 7.39-7.62 (m,5H), 7.67 (m, 1H), 8.42 (d, 1H), 8.56 (s, 1H), 9.18 (d, 1H), 10.99 (s,1H).

Example 134

Example 134 was prepared using a procedure similar to that used toprepare Example 20 where potassium 4-(piperidin-1-yl)nicotinate, whichwas prepared similarly to potassium 4-morpholinonicotinate from Example133 step a, was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MSm/z: 480.4 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 1.57 (s, 4H), 3.15 (s,4H), 5.15 (d, 1H), 7.15 (d, J=6.5 Hz, 1H), 7.19-7.40 (m, 3H), 7.40-7.60(m, 5H), 7.62-7.71 (m, 1H), 8.35 (d, J=6.5 Hz, 1H), 8.52 (s, 1H), 9.21(d, J=8.6 Hz, 1H), 10.99 (s, 1H).

Example 135

Example 135 Step a

A solution of the 3-chloro-5-fluoropicolinic acid (500 mg, 2.85 mmol),H₂SO₄ (1 mL) in EtOH (5 mL) was stirred at 80° C. for 4 hours. Then H₂O(20 ml) was added to the mixture and it was extracted with EtOAc (×3).The organic layer was dried and by reverse phase C18 columnchromatography (MeCN/H₂O) to give ethyl 3-chloro-5-fluoropicolinate asoff-white solid (400 mg, 69%). ESI-MS m/z: 203.9 [M+H]⁺.

Example 135 Step b

A solution of ethyl 3-chloro-5-fluoropicolinate (100 mg, 0.49 mmol),morpholine (43 mg, 0.49 mmol), K₂CO₃ (135 mg, 0.98 mmol) in DMSO (5 mL)was stirred at 100° C. for 2 hours. Then H₂O (20 ml) was added to themixture and it was extracted with EtOAc (×3). The organic layer wasdried and purified by reverse phase C18 column chromatography (MeCN/H₂O)to give ethyl 3-chloro-5-morpholinopicolinate as off-white solid (120mg, 91%). ESI-MS m/z: 270.9 [M+H]⁺.

Example 135 Step c

A solution of ethyl 3-chloro-5-morpholinopicolinate (120 mg, 0.44 mmol),hydrazine hydrate (1 mL) in EtOH (3 mL) was stirred at 80° C. for 1hour. The solution was concentrated and purified by reverse phase C18column chromatography (MeCN/H₂O) to give3-chloro-5-morpholinopicolinohydrazide as off-white solid (100 mg, 89%).ESI-MS m/z: 279.0[M+H]⁺.

Example 135 Step d

Example 135 was prepared using a procedure similar to that used toprepare Example 21 where 3-chloro-5-morpholinopicolinohydrazide was usedin place of tetrahydro-2H-pyran-4-carbohydrazide. ESI-MS m/z: 516.2[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 3.28-3.38 (m, 4H), 3.73-3.75 (m,4H), 5.15-5.17 (d, J=8.0 Hz, 1H), 7.26-7.29 (m, 1H), 7.33-7.36 (m, 2H),7.44-7.55 (m, 6H), 7.66-7.69 (m, 1H), 8.40-8.41 (m, 1H), 9.15-9.17 (m,1H), 10.99 (s, 1H).

Example 136

Example 136 Step a

A solution of 3,5-difluoropicolinic acid (3.3 g, 20.75 mmol), H₂SO₄ (5mL) in EtOH (20 mL) was stirred for 2 hours at 80° C. Then solvent wasremoved. The residue was diluted with EtOAc and it was washed with brine(×2). The organic layers was concentrated to give ethyl3,5-difluoropicolinate as a pale yellow solid (3.44 g, 88%). ESI-MS m/z:188.0 [M+H]⁺.

Example 136 Step b

A solution of ethyl 3,5-difluoropicolinate (3.1 g, 16.6 mmol),morpholine (1.44 g, 16.6 mmol) and K₂CO₃ (6.87 g, 49.8 mmol) in DMF (4mL) and DMSO (6 mL) was stirred for overnight at room temperature. Itwas poured into water and extracted with EtOAc. The organic layer wasdried over Na₂SO₄ and concentrated to give a mixture of ethyl5-fluoro-3-morpholinopicolinate and the isomer ethyl3-fluoro-5-morpholinopicolinate as a pale yellow solid (3.37 g). ESI-MSm/z: 255.2 [M+H]⁺.

Example 136 Step c

A solution of the mixture of isomers from step b (3.37 g, 13.3 mmol) andNaOH (796 mg, 19.9 mmol) in THF (10 mL) and H₂O (15 mL) was stirred for2 hours at room temperature. It was adjusted pH to 2-3 with HCl andpurified by Prep-HPLC (MeCN/H₂O) to give 817 mg of the desired compound5-fluoro-3-morpholinopicolinic acid as a white solid. ESI-MS m/z:227.0[M+H]⁺.

Example 136 Step d

A solution of 5-fluoro-3-morpholinopicolinic acid (817 mg, 3.62 mmol)and NH₂NHBoc (956 mg, 7.24 mol), DIPEA (934 mg, 7.24 mol) and HATU (1.44g, 3.80 mol) in DMF (10 mL) was stirred for half an hour at roomtemperature. It was diluted with H₂O (×3), extracted with EtOAc andpurified by reverse phase C18 column chromatography (MeCN/H₂O) to givetert-butyl 2-(5-fluoro-3-morpholinopicolinoyl)hydrazine-1-carboxylate asa need amount white solid. ESI-MS m/z: 341.2[M+H]⁺.

Example 136 Step e

A solution of tert-butyl2-(5-fluoro-3-morpholinopicolinoyl)hydrazine-1-carboxylate in EA (10 mL)was added HCl (3 mL, cone.). Then it was stirred for half an hour atroom temperature. Solvent was removed and the residue was purified byreverse phase C18 column chromatography (MeCN/H₂O) to give5-fluoro-3-morpholinopicolinohydrazide as a pale yellow solid (293 mg).ESI-MS m/z: 241.0[M+H]⁺.

Example 136 Step f

The above compound(S)-3-amino-5-phenyl-1,3-dihydro-2H-benzo[e]j[1,4]diazepin-2-one (A) wasmade several ways including the procedures described by Sherrill andSugg (J. Org. Chem. 1995, 60, 730-734), Rittle and Evans (TetrahedronLett. 1987, 28, 521-522), and the method described below.

Neat (R)-3-chloro-1-phenylpropan-1-ol (12.6 g, 73.8 mmol) was dissolvedin morpholine (60 mL) and the mixture was heated to 80° C. overnight.The mixture was cooled to rt, diluted with EtOAc, and washed with waterand brine. The organic layer was dried (Na₂SO₄), concentrated, andpumped on the high vacuum for 3 h. The material(R)-3-morpholino-1-phenylpropan-1-ol (14.0 g, 86%) was used directlywithout further purification.

Example 136 Step g

Solid p-nitrophenyl chloroformate (6.4 g, 41.1 mmol) was added to a DCMsolution (200 mL) of (R)-3-morpholino-1-phenylpropan-1-ol (7.0 g, 31.6mmol) and i-Pr₂NEt (8.3 mL, 47.4 mmol) and the mixture was stirred at rtovernight. The mixture was diluted with DCM, and washed with water andbrine, dried (Na₂SO₄), concentrated, and purified via columnchromatography to give the desired material(R)-3-morpholino-1-phenylpropyl (4-nitrophenyl) carbonate (10.2 g, 84%)as a yellow gum which will be used directly for the next step.

Example 136 Step h

Neat i-Pr₂NEt (4.1 mL, 23.2 mmol) was added to a DMF solution (140 mL)of (R)-3-morpholino-1-phenylpropyl (4-nitrophenyl) carbonate (6.9 g,17.9 mmol) and racemic amine(Z)-3-amino-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one (4.5 g, 17.9mmol) and the mixture was heated to 60° C. overnight. The mixture wascooled to rt, diluted with EtOAc, and washed with water and brine, dried(Na₂SO₄), concentrated, and purified via column chromatography (0-100%EtOAc/hexanes) to give the (R)-3-morpholino-1-phenylpropyl((S)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)carbamate(3.92 g, 44% yield, first and less polar spot) and(R)-3-morpholino-1-phenylpropyl((R)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)carbamate(3.56 g, 40% yield, second and more polar spot) as light yellow solids.ESI MS m/z=499.2395 [M+H]⁺ for R)-3-morpholino-1-phenylpropyl((S)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)carbamateand m/z=499.2379 [M+H]⁺ for (R)-3-morpholino-1-phenylpropyl((P)-2-oxo-5-phenyl-2,3-dihydro-1-benzo[e][1,4]diazepin-3-yl)carbamate.

Example 136 Step i

Neat (R)-3-morpholino-1-phenylpropyl((S)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)carbamate(4.4 g, 8.8 mmol) was dissolved in 33% HBr in AcOH (30 mL) and themixture was stirred at rt. After 2 h, the mixture became heterogeneousand the solution was cooled with ice bath and adjusted to pH ˜8 byadding saturated aqueous NaHCO₃ dropwise. After overnight, a white solidwas precipitated which was filtered, washed with cold water, cold MeOHand dried under high vacuum to afford pure(S)-3-amino-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one (A)(2.81 g, 79% yield) as a white solid. ESI MS m/z=252.1529 [M+H]⁺. ee%=98.4% (retention time 9.39 min, Method A); [α]_(D)=−195.56 (c=0.19,MeOH).

Example 136 Step j

Compound (R)-3-morpholino-1-phenylpropyl((R)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)carbamate(2.0 g, 4.0 mmol) was dissolved in MeOH (40 mL), and then 25% wt NaOMein MeOH (2.2 mL) was slowly added. The resulting mixture was stirred atrt for 20 hrs and confirmed with ¹H NMR that the ratio of diastereomerswas near 1:1. Diluted with EtOAc, washed with brine, dried andevaporated. The residue was purified by combiflash eluting with 0-10%MeOH/DCM to obtain (R)-3-morpholino-1-phenylpropyl((S)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)carbamate(0.90 g, 45% yield) and recycled (R)-3-morpholino-1-phenylpropyl((R)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)carbamate(0.84 g, 42% yield). The (R)-3-morpholino-1-phenylpropyl((S)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)carbamatewas re-subjected to example 136 step i to obtain the desired(S)-3-amino-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one.

Example 136 Step k

CDI (196 mg, 1.2 mmol) was added to a solution of(S)-3-amino-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one (A) (276mg, 1.1 mmol) in MeCN (3 mL) and DMF (0.6 mL), and then it was stirredfor 1 hour at room temperature. The compound from step e (293 mg, 1.2mmol) was added and then stirred for 48 hours. The crude product waspurified by reverse phase C18 column chromatography (MeCN/H₂O) to give(S)-2-(5-fluoro-3-morpholinopicolinoyl)-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)hydrazine-1-carboxamideas a light yellow solid (371 mg). ESI-MS m/z: 518.3 [M+H]⁺.

Example 136 Step l

A solution of(S)-2-(5-fluoro-3-morpholinopicolinoyl)-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)hydrazine-1-carboxamide(371 mg, 0.72 mmol), DMAP (20 mg) and TEA (181 mg, 1.78 mmol) in DCM (5mL) was added TsCl (204 mg, 1.07 mmol). It was stirred for 1 hour beforeconcentrated. The crude product was purified by Prep-HPLC (MeCN/H₂O) togive(S)-3-((5-(5-fluoro-3-morpholinopyridin-2-yl)-1,3,4-oxadiazol-2-yl)amino)-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-oneas a white solid (122 mg, 34%). ESI-MS m/z: 500.4 [M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 2.07 (s, 1H), 2.85-3.07 (m, 4H), 3.61-3.78 (m, 4H), 5.17(d, 1H), 7.06-7.81 (m, 9H), 8.34 (d, 1H), 9.21 (d, 1H), 10.97 (s, 1H).

Examples 137 and 138

Examples 137 and 138 Step a

A solution of 3,5-difluoropicolinic acid (1.60 g, 10.0 mol), morpholine(0.870 g, 10.0 mol) and K₂CO₃ (2.42 g, 176 mol) in DMSO (15 mL) wasstirred for 1 hour at 100° C. It was purified by reverse phase C18column chromatography (MeCN/H₂O) to give the mixture of3-fluoro-5-morpholinopicolinic acid and 5-fluoro-3-morpholinopicolinicacid as a yellow solid (1.90 g, 84%). ESI-MS m/z: 226.1 [M+H]⁺.

Examples 137 and 138 Step b

Examples 137 and 138 were prepared using a procedure similar to thatused to prepare Example 20 where 3-fluoro-5-morpholinopicolinic acid and5-fluoro-3-morpholinopicolinic acid were used, respectively, in place of5-chlorofuran-2-carboxylic acid. Example 137: ESI-MS m/z: 500.3 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 3.32 (t, J=4.9 Hz, 4H), 3.76 (t, J=4.9 Hz,4H), 5.17 (d, J=8.5 Hz, 1H) 7.61-7.17 (m, 9H), 7.82-7.62 (m, 1H),8.36-8.22 (m, 1H), 9.18 (d, J=8.6 Hz, 1H), 10.99 (s, 1H). Example 138:ESI-MS m/z: 500.2[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 3.10-2.88 (m, 4H),3.71 (dd, J=5.9, 3.3 Hz, 4H), 5.19 (d, J=8.6 Hz, 1H), 7.44-7.23 (m, 3H),7.76-7.44 (m, 7H), 8.36 (d, J=2.3 Hz, 1H), 9.25 (d, J=8.6 Hz, 1H), 11.00(s, 1H).

Example 139

Example 139 was prepared using a procedure similar to that used toprepare Example 20 where 3-morpholino-5-(trifluoromethyl)picolinic acid,which was prepared similarly to2-chloro-4-(1H-1,2,4-triazol-1-yl)benzoic acid from Example 128 step a,was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 550.4[M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 3.09 (d, J=4.6 Hz, 4H), 3.73 (d,J=4.6 Hz, 3H), 5.22 (d, J=8.4 Hz, 1H), 7.22-7.44 (m, 3H), 7.44-7.65 (m,5H), 7.66-7.80 (m, 1H), 7.91 (d, J=1.9 Hz, 1H), 8.71 (s, 1H), 9.43 (d,J=8.6 Hz, 1H), 11.01 (s, 1H).

Example 140

Example 140 was prepared using a procedure similar to that used toprepare Example 20 where 5-cyano-3-morpholinopicolinic acid, which wasprepared similarly to 2-chloro-4-(1H-1,2,4-triazol-1-yl)benzoic acidfrom Example 128 step a, was used in place of 5-chlorofuran-2-carboxylicacid. ESI-MS m/z: 507.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 3.02-3.04(m, 4H), 3.71-3.73 (m, 4H), 5.19-5.21 (d, J=8.0 Hz, 1H), 7.24-7.28 (m,1H), 7.30-7.37 (m, 5H), 7.42-7.90 (m, 1H), 8.00-8.13 (m, 1H), 8.47 (s,1H), 9.42-9.44 (m, 2H), 10.99 (s, 1H).

Example 141

Example 141 Step a

A solution of 3-fluoroisonicotinic acid (1.30 g, 1.0 mol), piperidine(1.16 g, 13.3 mol) and K₂CO₃ (2.25 g, 17.6 mol) in DMSO (15 mL) wasstirred for 1 hour at 120° C. It was purified by reverse phase C18column chromatography (MeCN/H₂O) to give 3-(piperidin-1-yl)isonicotinicacid as a white solid (1.12 g, 49%). ESI-MS m/z: 207.1 [M+H]⁺.

Example 141 Step b

Example 141 was prepared using a procedure similar to that used toprepare Example 20 where 3-(piperidin-1-yl)isonicotinic acid was used inplace of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 480.0 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 2.97 (s, 3H), 5.18 (d, J=8.3 Hz, 1H), 7.13-7.82(m, 11H), 8.22 (d, J=1.9 Hz, 1H), 9.47 (d, J=8.4 Hz, 1H), 11.00 (s, 1H).

Example 142

Example 142 was prepared using a procedure similar to that used toprepare Example 20 where 3-morpholinoisonicotinic acid, which wasprepared similarly to 3-(piperidin-1-yl)isonicotinic acid from Example141 step a, was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MSm/z: 482.3 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 3.05 (t, J=4.4 Hz, 4H),3.75 (t, J=4.5 Hz, 4H), 5.22 (d, J=8.5 Hz, 1H), 7.43-7.18 (m, 2H), 7.51(ddt, J=14.6, 9.1, 5.2 Hz, 5H), 7.85-7.65 (m, 2H), 8.49 (d, J=37.4 Hz,2H), 9.46 (d, J=8.5 Hz, 1H), 11.04 (s, 1H).

Example 143

Example 143 was prepared using a procedure similar to that used toprepare Example 20 where 3-morpholinopyrazine-2-carboxylic acid, whichwas prepared similarly to 3-(piperidin-1-yl)isonicotinic acid fromExample 141 step a, was used in place of 5-chlorofuran-2-carboxylicacid. ESI-MS m/z: 483.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 3.27-3.33(m, 4H), 3.67-3.70 (m, 4H), 5.17-5.19 (d, J=8.0 Hz, 1H), 7.26-7.28 (m,1H), 7.30-7.36 (m, 2H), 7.44-7.55 (m, 5H), 8.22-8.23 (m, 1H), 8.35 (s,1H), 9.33-9.35 (d, J=8.0 Hz, 1H), 10.99 (s, 1H).

Example 144

Example 144 Step a

A solution of 2-chloro-6-methylnicotinic acid (855 mg, 5 mmol), K₂CO₃(1.38 g, 10 mmol) and morpholine (2 mL) in DMF (20 mL) was stirred for 3hours at 130° C. Solid was filtered out and the solvent were removed andthe residue was washed with Et₂O (50 mL) to give6-methyl-2-morpholinonicotinic acid as a white solid (666 mg, 60%).ESI-MS m/z: 223.1 [M+H]⁺.

Example 144 Step b

Example 144 was prepared using a procedure similar to that used toprepare Example 20 where 6-methyl-2-morpholinonicotinic acid was used inplace of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 496.1 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 2.43 (s, 3H), 3.14 (m, 4H), 3.64-3.74 (m, 4H),5.16 (d, J=8.7 Hz, 1H), 6.92 (d, J=7.7 Hz, 1H), 7.24-7.41 (m, 3H),7.41-7.62 (m, 5H), 7.69 (m, 1H), 7.86 (d, J=7.7 Hz, 1H), 9.14 (d, J=8.8Hz, 1H), 11.00 (s, 1H).

Example 145

Example 145 Step a

A solution of 2-chloro-5-fluoronicotinic acid (1050 mg, 6 mmol) andmorpholine (3 mL) in DMF (15 mL) was stirred for 1 hour at 120° C. Thesolvent was removed to give 5-fluoro-2-morpholinonicotinic acid as awhite solid (904 mg, 67%). ESI-MS m/z: 227.1 [M+H]⁺.

Example 145 Step b

A solution of 5-fluoro-2-morpholinonicotinic acid (904 mg, 4 mmol) andH₂SO₄ (2 mL) in EtOH (50 mL) was stirred for 18 hours at 80° C. Then itwas adjusted to PH=9, extracted with EtOAc (3×), dried Na₂SO₄, filteredto give ethyl 5-fluoro-2-morpholinonicotinate as a white solid (762 mg,75%). ESI-MS m/z: 255.1 [M+H]⁺.

Example 145 Step c

A solution of ethyl 5-fluoro-2-morpholinonicotinate (762 mg, 3 mmol) andNH₂NH₂.H₂O (3 mL) in EtOH (10 mL) was stirred for 18 hours at 80° C. Thesolvent was removed and it was washed with Et₂O (20 mL) to give5-fluoro-2-morpholinonicotinohydrazide as a white solid (480 mg, 67%).ESI-MS m/z: 241.2 [M+H]⁺.

Example 145 Step d

Example 145 was prepared using a procedure similar to that used toprepare Example 21 where 5-fluoro-2-morpholinonicotinohydrazide was usedin place of tetrahydro-2H-pyran-4-carbohydrazide. ESI-MS m/z:500.1[M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 3.09 (m, 4H), 3.70 (m, 4H),5.18 (d, J=8.5 Hz, 1H), 7.24-7.45 (m, 3H), 7.42-7.75 (m, 6H), 7.94 (m,1H), 8.43 (d, J=3.0 Hz, 1H), 9.29 (d, J=8.6 Hz, 1H), 11.01 (s, 1H).

Example 146

Example 146 was prepared using a procedure similar to that used toprepare Example 20 where 2-morpholino-5-(trifluoromethyl)nicotinic acid,which was prepared similarly to 3-(piperidin-1-yl)isonicotinic acid fromExample 141 step a, was used in place of 5-chlorofuran-2-carboxylicacid. ESI-MS m/z: 550.4 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 3.31 (d,J=3.7 Hz, 4H), 3.68 (m, 4H), 5.14 (d, J=6.1 Hz, 1H), 7.19-7.39 (m, 3H),7.41-7.57 (m, 5H), 7.66 (m, 1H), 8.15 (d, J=2.4 Hz, 1H), 8.66 (m, 1H),9.21 (s, 1H), 10.97 (s, 1H).

Example 147

Example 147 Step a

A solution of 4-fluoro-2-(trifluoromethyl)benzoic acid (500 mg, 2.5mol), HATU (1.90 g, 5 mmol), DIPEA (650 mg, 5 mmol) and BnOH (200 uL) inDMF (10 mL) was stirred for 0.5 hour. It was added water, extracted byEtOAc to give 300 mg (crude) of benzyl4-fluoro-2-(trifluoromethyl)benzoate as yellow oil, which was useddirectly in the next step.

Example 147 Step b

A solution of benzyl 4-fluoro-2-(trifluoromethyl)benzoate (300 mg,crude) in morpholine (5 mL) was stirred for 1 hour at 100° C. Themixture was added water and extracted by EA to give desired compoundbenzyl 4-morpholino-2-(trifluoromethyl)benzoate as yellow oil (1.07 g,crude). ESI-MS m/z: 366.2 [M+H]⁺.

Example 147 Step c

A solution of benzyl 4-morpholino-2-(trifluoromethyl)benzoate (1.07 g,crude), NH₂NH₂.H₂O (10 ml) in EtOH (10 mL) was stirred at 80° C. for 1hour. The solvent was removed and the crude product was purified byreverse phase C18 column chromatography (MeCN/H₂O) to give desiredcompound 4-morpholino-2-(trifluoromethyl)benzohydrazide as a white solid(139 mg). ESI-MS m/z: 290.1 [M+H]⁺.

Example 147 Step d

Example 147 was prepared using a procedure similar to that used toprepare Example 21 where 4-morpholino-2-(trifluoromethyl)benzohydrazidewas used in place of tetrahydro-2H-pyran-4-carbohydrazide. ESI-MS m/z:549.2[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ3.32-3.34 (m, 4H), 3.65-3.82 (m,4H), 5.13 (d, J=8.5 Hz, 1H), 7.23-7.41 (m, 5H), 7.41-7.61 (m, 5H), 7.67(m, 1H), 7.75 (d, J=9.4 Hz, 1H), 9.07 (d, J=8.6 Hz, 1H), 10.99 (s, 1H).

Example 148

Example 148 Step a

A solution of 2-chloro-3-fluorobenzoic acid (1 g, 5.75 mmol) and H₂SO₄(1 mL) in EtOH (10 mL) were refluxed for 16 hours. It was concentratedand purified by reverse phase C18 column chromatography (MeCN/H₂O) togive ethyl 2-chloro-3-fluorobenzoate as a yellow oil (1.1 g, 95%).ESI-MS m/z: 202.9[M+H]⁺.

Example 148 Step b

A solution of ethyl 2-chloro-3-fluorobenzoate (1.1 g, 5.44 mmol) inmorpholine (neat) (6 ml) was stirred overnight at 120° C. It wasconcentrated under vacuum and the crude product was purified by prep-TLC(PE/EA=2/1) to give ethyl 3-fluoro-2-morpholinobenzoate a yellow solid(0.25 g, 18%). ESI-MS m/z: 254.0[M+H]⁺.

Example 148 Step c

A solution of ethyl 3-fluoro-2-morpholinobenzoate (0.25 g, 0.99 mmol)and NH₂NH₂. H₂O (1 mL) in EtOH (10 mL) was refluxed overnight. The crudeproduct was purified by reverse phase C18 column chromatography(MeCN/H₂O) to give 3-fluoro-2-morpholinobenzohydrazide as a white solid(0.16 g, 68%). ESI-MS m/z: 240.0[M+H]⁺.

Example 148 Step d

Example 148 was prepared using a procedure similar to that used toprepare Example 21 where 3-fluoro-2-morpholinobenzohydrazide was used inplace of tetrahydro-2H-pyran-4-carbohydrazide. ESI-MS m/z: 499.0[M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 3.02 (m, 4H), 3.55-3.73 (m, 4H), 5.19 (d,J=8.5 Hz, 1H), 7.24-7.62 (m, 11H), 7.62-7.74 (m, 1H), 9.18 (d, J=8.6 Hz,1H), 11.02 (s, 1H).

Examples 149 and 150

Examples 149 and 150 were prepared using a procedure similar to thatused to prepare Example 20 where 2-fluoro-6-morpholinonicotinic acid and6-fluoro-2-morpholinonicotinic acid, which were prepared similarly to3-fluoro-5-morpholinopicolinic acid and 5-fluoro-3-morpholinopicolinicacid in Examples, 137 and 138, were used, respectively, in place of5-chlorofuran-2-carboxylic acid. Example 137: ESI-MS m/z: 500.5[M+H]⁺.¹H NMR (300 MHz, DMSO-d₆) δ 3.58 (d, J=4.8 Hz, 4H), 3.69 (m, 4H), 5.13(d, J=8.6 Hz, 1H), 6.87 (d, J=8.8 Hz, 1H), 7.21-7.39 (m, 3H), 7.41-7.57(m, 5H), 7.58-7.74 (m, 1H), 8.01 (m 1H), 9.02 (d, J=8.6 Hz, 1H), 10.97(s, 1H). Example 138: ESI-MS m/z: 500.5[M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆)δ 3.09-3.23 (m, 4H), 3.66 (m, 4H), 5.14 (d, J=8.5 Hz, 1H), 6.70 (m, 1H),7.21-7.40 (m, 3H), 7.39-7.59 (m, 5H), 7.67 (m, 1H), 8.08 (m, 1H), 8.45(s, 0.35H), 9.15 (d, J=8.6 Hz, 1H), 10.94 (s, 1H).

Example 151

Example 151 Step a

A solution of 6-fluoro-2-morpholinonicotinic acid, which was preparedsimilarly as 5-fluoro-2-morpholinonicotinic acid described in Example145 step a, (280 mg, 1.22 mmol), tert-butyl hydrazinecarboxylate (161mg, 1.22 mmol), HATU (464 mg, 1.22 mmol) and DIPEA (0.34 mL, 2.04 mmol)in DMF (5 mL) was stirred for 1 hour at room temperature. It waspurified by reverse phase C18 column chromatography (MeCN/H₂O) to givetert-butyl 2-(6-fluoro-2-morpholinonicotinoyl)hydrazine-1-carboxylate asa white solid (400 mg, 96%). ESI-MS m/z: 341.2 [M+H]⁺.

Example 151 Step b

A solution of tert-butyl2-(6-fluoro-2-morpholinonicotinoyl)hydrazine-1-carboxylate (400 mg, 1.18mmol) and conc. HCl (0.4 mL) in EA (2 mL) was stirred for 1 hour. It wasconcentrated, adjusted to PH=7-8 with saturated aqueous NaHCO₃. Thecrude product was purified by reverse phase C18 column chromatography(MeCN/H₂O) to give 6-fluoro-2-morpholinonicotinohydrazide as a paleyellow solid (210 mg, 75%). ESI-MS m/z: 241.2 [M+H]⁺.

Example 151 Step c

CDI (160 mg, 0.96 mmol) was added to a solution of(S)-3-amino-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one (A) fromExample 136 steps f and/or i (242 mg, 0.96 mmol), in MeCN (3 mL) and DMF(0.6 mL), and then stirred for 1 hour at room temperature. Then6-fluoro-2-morpholinonicotinohydrazide (210 mg, 0.88 mmol) was added andthen stirred for 48 hours at room temperature. The crude product waspurified by reverse phase C18 column chromatography (MeCN/H₂O) to give(S)-2-(6-fluoro-2-morpholinonicotinoyl)-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)hydrazine-1-carboxamideas a light yellow solid (300 mg). ESI-MS m/z: 518.2 [M+H]⁺.

Example 151 Step d

A solution of(S)-2-(6-fluoro-2-morpholinonicotinoyl)-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)hydrazine-1-carboxamide(300 mg, 0.58 mmol), TsCl (166 mg, 0.87 mmol) and TEA (117 mg, 1.16mmol) in DCM (5 mL) was stirred for 1 hour before concentrated. Thecrude product was purified by Prep-HPLC (MeCN/H₂O) to give(S)-3-((5-(6-fluoro-2-morpholinopyridin-3-yl)-1,3,4-oxadiazol-2-yl)amino)-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-oneas a white solid (59 mg, 20%). ESI-MS m/z: 500.3 [M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 3.11-3.23 (m, 4H), 3.66 (m, 4H), 5.14 (d, J=8.6 Hz, 1H),6.70 (m, 1H), 7.18-7.38 (m, 3H), 7.41-7.59 (m, 5H), 7.67 (m, 1H), 8.08(m, 1H), 9.14 (d, J=8.6 Hz, 1H), 10.96 (s, 1H).

Example 152

Example 152 Step a

A solution of 2-morpholino-4-(trifluoromethyl)benzoic acid (1.0 g, 0.35mol), H₂SO₄ (3 mL) in EtOH (10 mL) was stirred for 4 hours at 80° C. Itwas diluted with water, extracted with EA (×3), washed with brine (×2).The organic layer was dried and concentrated to give 869 mg (crude) ofethyl 2-morpholino-4-(trifluoromethyl)benzoate as yellow oil, which wasused directly in the next step. ESI-MS m/z: 304.2 [M+H]⁺.

Example 152 Step b

A solution of the compound from step 1 (869 mg, 2.87 mmol) andNH₂NH₂.H₂O (5 mL) in EtOH (15 mL) was refluxed for 13 hours. The crudeproduct was purified by reverse phase C18 column chromatography(MeCN/H₂O) to give desired compound as a white solid (651 mg, 78%).ESI-MS m/z: 290.1 [M+H]⁺.

Example 152 Step c

CDI (180 mg, 0.80 mmol) was added to a solution of(S)-3-amino-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one (A) fromExample 136 steps f and/or i (200 mg, 0.80 mmol) in MeCN (3 mL) and DMF(0.6 mL) and then stirred for 1 hour. The compound from step b (315 mg,1.10 mmol) was added and then stirred for 72 hours. The crude productwas purified by reverse phase C18 column chromatography (MeCN/H₂O) togive desired compound as a light yellow solid (283 mg, 63%). ESI-MS m/z:567.3 [M+H]⁺.

Example 152 Step d

A solution of the compound from step c (283 mg, 0.50 mmol), TsCl (285mg, 0.75 mmol) and TEA (0.5 mL) in DCM (5 mL) was stirred for 16 hoursbefore concentrated. The crude product was purified by Prep-HPLC(MeCN/H₂O) to give the title compound as a light yellow solid (205 mg,75%). ESI-MS m/z: 549.2 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 2.95 (dd,J=6.3, 3.0 Hz, 4H), 3.71 (dd, J=5.7, 3.5 Hz, 4H), 5.18 (d, J=8.5 Hz,1H), 7.18-7.63 (m, 10H), 7.67 (ddd, J=8.5, 7.1, 1.7 Hz, 1H), 7.86-7.98(m, 1H), 9.26 (d, J=8.6 Hz, 1H), 10.97 (s, 1H).

Example 153

Example 153 Step a

A solution morpholine (0.85 g, 9.8 mmol) in DMF (20 mL) was addeddropwise to methyl 2,6-dichloronicotinate (2 g, 9.8 mmol) in DMF (100mL). It was stirred for 1 hour at rt. The mixture was diluted withwater, extracted with EA (×3) and washed with brine (×2). The organiclayer was dried and concentrated. The residue was chromatographed(silica gel, PE:EA=10:1) to give methyl 6-chloro-2-morpholinonicotinateas light yellow solid (0.6 g, 24%). ESI-MS m/z: 257.2 [M+H]⁺.

Example 153 Step b

A solution of methyl 6-chloro-2-morpholinonicotinate (0.6 g, 2.34 mmol),Zn(CN)₂ (0.54 g, 4.68 mmol), Pd(PPh₃)₄ (0.53 g, 0.46 mmol) in DMF (30mL) was stirred for 2 hours at 80° C. under nitrogen. It was dilutedwith EA and washed with water (×2). The organic layer was dried,concentrated and purified by Prep-TLC (PE/EA=3:1) to give methyl6-cyano-2-morpholinonicotinate. ESI-MS m/z: 248.2[M+H]⁺.

Example 153 Step c

A solution of methyl 6-cyano-2-morpholinonicotinate, LiOH (0.1 g, 2.68mmol) in THF (5 mL) and water (2 mL) was stirred at room temperature for5 hours. The solvent was removed and the crude product was purified byreverse phase C18 column chromatography (MeCN/H₂O) to give6-cyano-2-morpholinonicotinic acid as a white solid (0.4 g). ESI-MS m/z:234.2 [M+H]⁺.

Example 153 Step d

Example 153 was prepared using a procedure similar to that used toprepare Example 151 where 6-cyano-2-morpholinonicotinic acid was used inplace of 6-fluoro-2-morpholinonicotinic acid. ESI-MS m/z: 507.4 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 3.21 (m, 4H), 3.71 (m, 4H), 5.19 (s, 1H),7.33 (m, 3H), 7.50 (m, 5H), 7.62 (d, J=7.8 Hz, 1H), 7.69 (m, 1H), 8.16(d, J=7.7 Hz, 1H), 9.38 (s, 1H), 10.91 (s, 1H).

Example 154

Example 154 Step a

A solution of compound 1 (940 mg, 4 mmol) and H₂SO₄ (2 mL) in EtOH (20mL) was stirred for 18 hours at 80° C. Then it was adjusted PH to 8-9,extracted with EA (3×), dried Na₂SO₄, filtered and concentrated to givedesired compound as a white solid (1052 mg, 100%). ESI-MS m/z: X [M+H]⁺.

Example 154 Step b

A solution of compound from step a (526 mg, 2 mmol), cyclopropylboronicacid (860 mg, 10 mmol), Pd(dppf)Cl₂ (146 mg, 0.2 mmol) and K₂CO₃ (550mg, 4 mmol) in dioxane (12 mL) was heated to 70° C. by microwave for 1.5hours. Then it was poured into water and extracted with EA (3×). Theresidue was purified by reverse phase C18 column chromatography(MeCN/H₂O) to give desired compound as brown oil. (315 mg, 70%). ESI-MSm/z: 225.9 [M+H]⁺.

Example 154 Step c

A solution of compound from step b (315 mg, 1.4 mmol) in morpholine (10mL) was stirred for 2 hours at 80° C. The solvents were removed and itwas purified by reverse phase C18 column chromatography (MeCN/H₂O) togive desired compound as brown oil. (331 mg, 86%). ESI-MS m/z: 277.2[M+H]⁺.

Example 154 Step d

Example 154 was prepared using a procedure similar to that used toprepare Example 152 where ethyl 6-cyclopropyl-2-morpholinonicotinate wasused in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI-MSm/z: 522.4 [M+H]⁺. ¹H NMR (300 MHz, Methanol-d₄) δ 0.87-1.13 (m, 4H),2.04 (m, 1H), 3.22 (m, 4H), 3.77 (m, 4H), 4.82 (s, 1H), 5.28 (s, 1H),6.92 (d, J=7.9 Hz, 1H), 7.22-7.71 (m, 9H), 7.87 (d, J=7.9 Hz, 1H).

Example 155

Example 155 Step a

A solution of the 2-chloro-6-oxo-1, 6-dihydropyridine-3-carboxylic acid(1.0 g, 5.78 mmol), H₂SO₄ (5 mL) in EtOH (20 mL) was stirred at 80° C.for 4 hours. Then H₂O (100 mL) was added to the mixture and it wasextracted with EA (×3). The organic layer was dried and purified byreverse phase C18 column chromatography (MeCN/H₂O) to give ethyl2-chloro-6-oxo-1,6-dihydropyridine-3-carboxylate as yellow oil (950 mg,81%). ESI-MS m/z: 201.9 [M+H]⁺.

Example 155 Step b

A solution of ethyl 2-chloro-6-oxo-1,6-dihydropyridine-3-carboxylate(402 mg, 2.0 mmol) in morpholine (5 mL) was stirred at 100° C. for 2hours. Then H₂O (20 mL) was added to the mixture and it was extractedwith EA (×3). The organic layer was dried and purified by reverse phaseC18 column chromatography (MeCN/H₂O) to give ethyl2-morpholino-6-oxo-1,6-dihydropyridine-3-carboxylate as yellow oil (450mg, 89%). ESI-MS m/z: 253.0 [M+H]⁺.

Example 155 Step c

A solution of ethyl 2-morpholino-6-oxo-1,6-dihydropyridine-3-carboxylate(400 mg, 1.58 mmol), iodomethane (1127 mg, 7.93 mmol), t-BuONa (303 mg,3.16 mmol) in DMF (10 mL) was stirred at rt for 2 hours. Then H₂O (20mL) was added to the mixture and it was extracted with EA (×3). Theorganic layer was dried and purified by flash to give ethyl1-methyl-2-morpholino-6-oxo-1,6-dihydropyridine-3-carboxylate as yellowoil (320 mg, 76%). ESI-MS m/z: 267.0 [M+H]⁺.

Example 155 Step d

Example 155 was prepared using a procedure similar to that used toprepare Example 152 where ethyl1-methyl-2-morpholino-6-oxo-1,6-dihydropyridine-3-carboxylate was usedin place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI-MS m/z:512.3 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 3.21-3.23 (d, J=6.0 Hz, 4H),3.67-3.70 (m, 4H), 3.88 (s, 1H), 5.12-5.15 (d, J=9.0 Hz, 1H), 6.40-6.42(d, J=6.0 Hz, 1H), 7.26-7.37 (m, 3H), 7.44-7.57 (m, 5H), 7.65-7.68 (m,1H), 7.70-7.86 (m, 1H), 9.01-9.04 (m, 1H), 10.96 (s, 1H).

Example 156

Example 156 Step a

Ethyl 2-morpholino-6-oxo-1,6-dihydropyridine-3-carboxylate, from Example155 step b, (500 mg, 1.98 mmol) was dissolved in DMF (10 mL) and cooledin an ice bath. NaH (105 mg, 2.62 mmol) was added and then SEMCl (420mg, 2.52 mmol) was added. The mixture was warmed to rt and stirred for 2hours. Water (10 mL) was added and the mixture was extracted with EA (20mL×3). The combined organic phase was dried over anhydrous Na₂SO₄ andconcentrated to give ethyl 2-chloro-6-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridine-3-carboxylate as yellow oil(510 mg, 67%). ESI-MS m/z: 383.2 [M+H]⁺.

Example 156 Step b

A solution of ethyl2-chloro-6-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridine-3-carboxylate(510 mg, 1.33 mmol) and NH₂NH₂.H₂O (10 mL) in EtOH (10 mL) was refluxedfor 5 hours. The mixture was then cooled to r.t. and concentrated. Theresidue was purified by reverse phase C18 column chromatography(MeCN/H₂O) to give2-chloro-6-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridine-3-carbohydrazideas a yellow solid (300 mg, 61%). ESI-MS m/z: 369.2 [M+H]⁺.

Example 156 Step c

CDI (132 mg, 0.81 mmol) was added to a solution of(S)-3-amino-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one (A) fromExample 136 steps f and/or i (186 mg, 0.74 mmol) in MeCN (3 mL) and DMF(0.6 mL) and then stirred for 1 hour. Then2-chloro-6-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridine-3-carbohydrazide (300 mg, 0.81mmol) was added and then stirred for 72 hours and then purified byreverse phase C18 column chromatography (MeCN/H₂O) to give(S)-2-(2-morpholino-6-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridine-3-carbonyl)-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)hydrazine-1-carboxamideas an off white solid (300 mg, 63%). ESI-MS m/z: 646.4 [M+H]⁺.

Example 156 Step d

A solution of(S)-2-(2-morpholino-6-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridine-3-carbonyl)-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)hydrazine-1-carboxamide(300 mg, 0.46 mmol), TsCl (132.8 mg, 0.69 mmol), DMAP (20 mg) and TEA(0.5 mL) in DCM (5 mL) was stirred for 2 hours and then it wasconcentrated. The crude product was purified by reverse phase C18 columnchromatography (MeCN/H₂O) to give(S)-3-((5-(2-morpholino-6-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridin-3-yl)-1,3,4-oxadiazol-2-yl)amino)-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-oneas a yellow solid (200 mg, 69%). ESI-MS m/z: 628.4 [M+H]⁺.

Example 156 Step e

(S)-3-((5-(2-morpholino-6-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridin-3-yl)-1,3,4-oxadiazol-2-yl)amino)-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one(200 mg, 0.32 mmol) was dissolved in DCM (8 mL) and cooled to 0° C. andTFA (4 mL) was added. The mixture was stirred at rt for 1 hour and thenconcentrated. The residue was dissolved in DCM and then concentrated fortwo cycles. The residue was purified by Prep-HPLC to give(S)-3-((5-(2-morpholino-6-oxo-1,6-dihydropyridin-3-yl)-1,3,4-oxadiazol-2-yl)amino)-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-oneas a white solid (51 mg, 32%). ESI-MS m/z: 498.2 [M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) 3.12 (t, J=4.7 Hz, 4H), 3.65 (t, J=4.6 Hz, 4H), 5.12 (d,J=8.7 Hz, 1H), 6.20 (d, J=8.4 Hz, 1H), 7.21-7.39 (m, 3H), 7.39-7.59 (m,5H), 7.60-7.78 (m, 2H), 8.96 (d, J=8.7 Hz, 1H), 10.96 (s, 1H), 11.12 (s,1H).

Example 157

Example 157 was prepared using a procedure similar to that used toprepare Example 151 where 4-cyano-2-morpholinobenzoic acid, which wasprepared in Example 131, was used in place of6-fluoro-2-morpholinonicotinic acid. ESI-MS m/z: 506.2 [M+H]⁺. ¹H NMR(300 MHz, DMSO-d₆) δ 2.94-2.97 (m, 4H), 3.67-3.74 (m, 4H), 5.20 (d,J=8.3 Hz, 1H), 7.34-7.75 (m, 11H), 7.86 (d, J=8.0 Hz, 1H), 9.31 (d,J=8.6 Hz, 1H), 11.00 (s, 1H).

Example 158

Example 158 step a:

A solution of ethyl 2-chloro-5-cyano-6-methylnicotinate (1 g, 4.5 mmol)and K₂CO₃ (1.24 g, 9 mmol) in morpholine (5 mL) was stirred for 3 hoursat 100° C. It was diluted with water and extracted with EA (×3). Theorganic layer was concentrated and the residue was purified by silicagel chromatography with EtOAc/PE to give 970 mg of desired compound asyellow solid. ESI-MS m/z: 276.2 [M+H]⁺.

Example 158 Step b

A solution of the compound from step 1 (100 mg, 0.36 mmol), LiOH.H₂O (31mg, 0.73 mmol), in THF (5 mL) and water (2 mL) was stirred at roomtemperature overnight. Then adjusted the pH to 2 by 0.5 M HCl. Solventwas removed. The crude product was purified by reverse phase C18 columnchromatography (MeCN/H₂O) to give desired compound as a pink solid (80mg, 89%). ESI-MS m/z: 248.2 [M+H]⁺.

Example 158 Step c

Example 158 was prepared using a procedure similar to that used toprepare Example 151 where 5-cyano-6-methyl-2-morpholinonicotinic acidwas used in place of 6-fluoro-2-morpholinonicotinic acid. ESI-MS m/z:521.5 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 2.55 (s, 3H), 3.33-3.40 (m,4H), 3.66 (m, 4H), 5.14 (d, J=8.5 Hz, 1H), 7.21-7.42 (m, 3H), 7.39-7.59(m, 5H), 7.67 (m, 1H), 8.16 (s, 1H), 9.17 (d, J=8.5 Hz, 1H), 10.98 (s,1H).

Example 159

Example 159 Step a

A solution of 4-fluoro-2-morpholinobenzoic acid, prepared in Example 127step a (2.25 g, 10 mmol) and H₂SO₄ (10 mL) in EtOH (50 mL) was stirredfor 18 hours at 80° C. The solvent was removed, H₂O (100 mL) was addedand it was extracted with EA (3×). The water layer was adjusted PH to9-10 and extracted with EA (3×). The organic layers were combined andconcentrated to give ethyl 4-fluoro-2-morpholinobenzoate as a whitesolid (1270 mg, 50%). ESI-MS m/z: 254.1 [M+H]⁺.

Example 159 Step b

Example 159 was prepared using a procedure similar to that used toprepare Example 152 where ethyl 4-fluoro-2-morpholinobenzoate was usedin place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI-MS m/z:499.3 [M+H]⁺. ¹H NMR (300 MHz, Methanol-d₄) δ 2.94-3.04 (m, 4H),3.77-3.87 (m, 4H), 5.30 (s, 1H), 6.82-7.02 (m, 2H), 7.23-7.83 (m, 10H).

Example 160

Example 160 Step a

A solution of the methyl 5-bromo-3-fluoropicolinate (1.0 g, 4.29 mmol),K₂CO₃ (1.2 g, 8.58 mmol) in morpholine (10 mL) was stirred at 120° C.for 2 hours. Then H₂O (150 mL) was added to the mixture and it wasextracted with EA (×3). The organic layer was dried and purified byreverse phase C18 column chromatography (MeCN/H₂O) to give desiredcompound as yellow oil (950 mg, 74%). ESI-MS m/z: 300.9 [M+H]⁺.

Example 160 Step b

A solution of the compound from step a (900 mg, 3.00 mmol), Pd(PPh₃)₄(693 mg, 0.60 mmol), Zn(CN)₂ (696 mg, 6.00 mmol) in DMF (5 mL) wasstirred at 120° C. for 2 hours. Then H₂O (20 ml) was added to themixture and it was extracted with EA (×3). The organic layer was driedand purified by reverse phase C18 column chromatography (MeCN/H₂O) togive desired compound as yellow oil (330 mg, 44%). ESI-MS m/z: 248.2[M+H]⁺.

Example 160 Step c

Example 160 was prepared using a procedure similar to that used toprepare Example 152 where methyl 5-cyano-3-morpholinopicolinate was usedin place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI-MS m/z:507.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 3.02-3.04 (m, 4H), 3.71-3.73(m, 4H), 5.19-5.21 (d, J=8.0 Hz, 1H), 7.26-7.30 (m, 1H), 7.34-7.36 (m,2H), 7.44-7.55 (m, 5H), 7.65-7.70 (m, 1H), 8.13 (s, 1H), 8.72 (s, 1H),9.42-9.45 (m, 1H), 10.98 (s, 1H).

Example 161

Example 161 Step a

A solution of methyl 5-chloropyrazine-2-carboxylate (1.0 g, 5.79 mmol)and morpholine (756 mg, 8.69 mmol) in DMSO (10 mL) was added K₂CO₃ (2.4g, 17.4 mmol). The mixture was heated to 100° C. for 4 hours and thencooled to r.t. Water (20 mL) was added and the mixture was extractedwith EA (20 mL×3). The combined organic phase was washed with water (20mL) and brine (20 mL). It was then dried over anhydrous Na₂SO₄ andconcentrated to give the desired product as a yellow solid (850 mg)which was used directly next step. ESI-MS m/z: 224.1 [M+H]⁺.

Example 161 Step b

Example 161 was prepared using a procedure similar to that used toprepare Example 152 where methyl 5-morpholinopyrazine-2-carboxylate wasused in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI-MSm/z: 483.2 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 3.62-3.79 (m, 8H), 5.17(d, J=7.8 Hz, 1H), 7.18-7.80 (m, 9H), 8.42 (s, 1H), 8.63 (s, 1H), 9.13(d, J=8.2 Hz, 1H), 10.83-10.93 (m, 1H).

Example 162

Example 162 Step a

A solution of ethyl 4-chloro-2-(trifluoromethyl)pyrimidine-5-carboxylate(0.5 g, 1.97 mmol) in morpholine (5 mL) was stirred for 1 hour at rt.The mixture was concentrated. The residue was purified by prep-TLC(PE:EA=2:1) to give desired compound as light yellow solid (0.6 g,100%). ESI-MS m/z: 306.2 [M+H]⁺.

Example 162 Step b

A solution of the compound from step 1 (600 mg, 1.97 mmol), LiOH (189mg, 7.88 mmol) in THF (5 mL) and water (5 mL) were stirred at 70° C. for3 hours. The solvent was removed and the crude product was purified byreverse phase C18 column chromatography (MeCN/H₂O) to give desiredcompound as a white solid (0.45 g, 82%). ESI-MS m/z: 278.1 [M+H]⁺.

Example 162 Step c

Example 162 was prepared using a procedure similar to that used toprepare Example 151 where4-morpholino-2-(trifluoromethyl)pyrimidine-5-carboxylic acid was used inplace of 6-fluoro-2-morpholinonicotinic acid. ESI-MS m/z: 551.6 [M+H]⁺.¹H NMR (300 MHz, DMSO-d₆) δ 3.50 (m, 4H), 3.70 (m, 4H), 5.18 (d, J=8.0Hz, 1H), 7.22-7.42 (m, 3H), 7.42-7.62 (m, 5H), 7.68 (m, 1H), 8.71 (s,1H), 9.31 (d, J=8.4 Hz, 1H), 11.02 (s, 1H).

Example 163

Example 163 Step a

A mixture of 2-aminopyridine (940 mg, 10 mmol) and ethyl glyoxalatesolution (50% solution in toluene) (2 mL, 10 mmol) was stirred at rt for2 min. THF (20 mL) and DABCO (1.12 g, 10 mmol) were subsequently added.The reaction mixture was cooled to 0-5° C. and TMSCN (1.25 mL, 1 mmol)was added. The mixture was heated under microwave irradiation at 120° C.After completion of the reaction (monitored by TLC, 15 min), the solventwas evaporated under vacuum. The residue was purified by reverse phaseC18 column chromatography (MeCN/H₂O) to give desired compound (600 mg)as yellow oil. ESI-MS m/z: 206.0 [M+H]⁺.

Example 163 Step b

A solution of the compound from step a (600 mg, 2.92 mmol),1-bromo-2-(2-bromoethoxy) ethane (1.01 g, 4.39 mmol) and Cs₂CO₃ (2.85 g,8.76 mmol) in DMA (20 mL) was stirred for 4 hours at 120° C. The crudeproduct was purified by reverse phase C18 column chromatography(MeCN/H₂O) to give desired compound as a yellow solid (500 mg). ESI-MSm/z: 276.2 [M+H]⁺.

Example 163 Step c

Example 163 was prepared using a procedure similar to that used toprepare Example 152 where ethyl3-morpholinoimidazo[1,2-a]pyridine-2-carboxylate was used in place ofethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI-MS m/z: 521.5[M+H]⁺. ¹H NMR (300 MHz, Methanol-d₄) δ 3.90 (t, J=4.6 Hz, 4H), 5.34 (s,1H), 7.08 (td, J=6.8, 1.2 Hz, 1H), 7.26-7.33 (m, 1H), 7.34-7.70 (m,10H), 8.46 (dt, J=7.0, 1.2 Hz, 1H).

Example 164

Example 164 Step a

A solution of methyl 1-methyl-4-nitro-1H-pyrazole-3-carboxylate (1.0 g,5.41 mmol) and Pd/C (200 mg) in MeOH (60 mL) was stirred for 1 hour at25° C. Pd/C was filtered out and the filtrate was concentrated to givedesired compound as a white solid (800 mg, 95%).

Example 164 Step b

A solution of compound from step a (775 mg, 5 mmol),1-chloro-2-(2-chloroethoxy)ethane (1420 mg, 10 mmol), KI (1660 mg, 10mmol) and K₂CO₃ (2070 mg, 15 mmol) in DMF (60 mL) was stirred for 3hours at 120° C. The solvent was removed and it was purified by reversephase C18 column chromatography (MeCN/H₂O) to give desired compound as alight yellow solid. (450 mg, 40%). ESI-MS m/z: 226.0 [M+H]⁺.

Example 164 Step c

Example 164 was prepared using a procedure similar to that used toprepare Example 152 where methyl1-methyl-4-morpholino-1H-pyrazole-3-carboxylate was used in place ofethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI-MS m/z: 485.4[M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 2.94 (m, 4H), 3.68 (m, 4H), 3.86 (d,J=2.2 Hz, 3H), 5.09-5.19 (m, 1H), 7.23-7.41 (m, 3H), 7.38-7.75 (m, 7H),9.05 (m, 1H), 10.91 (s, 1H).

Example 165

Example 165 Step a

A solution of ethyl 4-chloropyrimidine-5-carboxylate (0.90 g, 5.0 mmol)in morpholine (5 mL) was stirred for 1 hour at rt. The mixture wasconcentrated. The residue was purified by prep-TLC (PE:EA=2:1) to givedesired compound as light yellow solid (869 mg, 74%). ESI-MS m/z: 238.1[M+H]⁺.

Example 165 Step b

Example 165 was prepared using a procedure similar to that used toprepare Example 152 where ethyl 2-morpholinopyrimidine-5-carboxylate wasused in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI-MSm/z: 483.1 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 3.69 (d, J=4.9 Hz, 4H),3.81 (t, J=4.8 Hz, 4H), 5.14 (d, J=8.4 Hz, 1H), 7.21-7.42 (m, 3H),7.42-7.61 (m, 5H), 7.61-7.75 (m, 1H), 8.75 (s, 2H), 9.05 (d, J=8.6 Hz,1H), 10.98 (s, 1H).

Example 166

Example 166 was prepared using a procedure similar to that used toprepare Example 152 where ethyl2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrimidine-5-carboxylate, whichwas prepared similarly to ethyl 2-morpholinopyrimidine-5-carboxylate inExample 165 step a, was used in place of ethyl2-morpholino-4-(trifluoromethyl)benzoate. ESI-MS m/z: 509.2 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 1.66 (t, J=6.6 Hz, 2H), 1.84 (dd, J=8.5, 4.3Hz, 2H), 3.16 (dd, J=13.4, 2.5 Hz, 2H), 4.29 (d, J=13.0 Hz, 2H),4.37-4.55 (m, 2H), 5.14 (d, J=8.5 Hz, 1H), 7.24-7.40 (m, 3H), 7.43-7.58(m, 5H), 7.68 (ddd, J=8.4, 7.2, 1.6 Hz, 1H), 8.74 (s, 2H), 9.06 (d,J=8.5 Hz, 1H), 10.82-11.07 (m, 1H).

Example 167

Example 167 Step a

A solution morpholine (0.79 g) in DMF (20 mL) was added dropwise toethyl 2,4-dichloropyrimidine-5-carboxylate (2 g, 9.1 mmol) in DMF (100mL). It was stirred for 1 hour at rt. The mixture were diluted withwater, extracted with EA (×3), washed with brine (×2). The organic layerwas dried and concentrated. The residue was chromatographed (silica gel,PE:EA=10:1) to give desired compound as light yellow solid (1.0 g, 41%).ESI-MS m/z: 272.2 [M+H]⁺.

Example 167 Step b

A solution of the compound from step a (0.8 g, 3.0 mmol),cyclopropylboronic acid (360 mg, 4.2 mmol), Pd(DtBPF)Cl₂ (196 mg, 0.3mmol) and Cs₂CO₃ (1.47 g, 4.5 mmol) in dioxane (30 mL) was stirred for 3hours at 100° C. under nitrogen. It was diluted with EA, washed withwater (×2). The organic layer was dried, concentrated and purified byPrep-TLC (PE/EA=3:1) to give desired compound as a yellow solid (420 mg,50%). ESI-MS m/z: 278.2 [M+H]⁺.

Example 167 Step c

A solution of the compound from step b (400 mg, 1.44 mmol), LiOH (140mg, 5.78 mmol) in MeOH (2 mL) and water (2 mL) was stirred at roomtemperature for 5 hours. The solvent was removed and the crude productwas purified by reverse phase C18 column chromatography (MeCN/H₂O) togive desired compound as a white solid (200 mg, 50%). ESI-MS m/z: 250.2[M+H]⁺.

Example 167 Step d

Example 167 was prepared using a procedure similar to that used toprepare Example 151 where2-cyclopropyl-4-morpholinopyrimidine-5-carboxylic acid was used in placeof 6-fluoro-2-morpholinonicotinic acid. ESI-MS m/z: 523.4 [M+H]⁺. ¹H NMR(300 MHz, DMSO-d₆) δ 0.85-1.10 (m, 4H), 2.06 (m, 1H), 3.37 (q, J=3.6 Hz,4H), 3.64 (m, 4H), 5.13 (d, J=8.5 Hz, 1H), 7.22-7.41 (m, 3H), 7.41-7.60(m, 5H), 7.67 (m, 1H), 8.38 (s, 1H), 9.11 (d, J=8.5 Hz, 1H), 10.98 (s,1H).

Example 168

Example 168 was prepared using a procedure similar to that used toprepare Example 152 where methyl 5-bromo-3-morpholinopicolinate,prepared in Example 160 step a, was used in place of ethyl2-morpholino-4-(trifluoromethyl)benzoate. ESI-MS m/z: 560.1 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 3.03 (t, J=4.6 Hz, 4H), 3.72 (t, J=4.6 Hz, 4H),5.20 (d, J=8.5 Hz, 1H), 7.25-7.60 (m, 8H), 7.69 (m, 1H), 7.86 (d, J=2.0Hz, 1H), 8.46 (d, J=1.8 Hz, 1H), 9.27 (d, J=8.6 Hz, 1H), 10.99 (d,J=12.7 Hz, 1H).

Example 169

Example 169 Step a

A solution of methyl 5-bromo-3-morpholinopicolinate, prepared in Example160 step a, (753 mg, 2.5 mmol), K₂CO₃ (1.73 g, 12.5 mmol),cyclopropylboronic acid (1.07 g, 12.5 mmol) and Pd(dppf)Cl₂ (183 mg,0.25 mmol) in dioxane (10 mL) was stirred for 1 hour at 80° C. in themicrowave. It was concentrated under vacuum and diluted with water (100mL). The resulting solution was extracted with EA (100 mL×3). Theorganic layer was dried and concentrated to give 1.0 g (crude) ofdesired compound, which was used directly in the next step. ESI-MS m/z:263.0 [M+H]⁺.

Example 169 Step b

Example 169 was prepared using a procedure similar to that used toprepare Example 152 where methyl 5-cyclopropyl-3-morpholinopicolinatewas used in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate.ESI-MS m/z: 522.4 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (dt, J=6.8,3.3 Hz, 2H), 1.07 (dt, J=8.6, 3.2 Hz, 2H), 2.04 (tt, J=8.7, 5.0 Hz, 1H),2.98 (t, J=4.6 Hz, 4H), 3.70 (t, J=4.5 Hz, 4H), 5.19 (d, J=8.7 Hz, 1H),7.22-7.41 (m, 4H), 7.44-7.58 (m, 5H), 7.69 (ddd, J=8.5, 7.1, 1.8 Hz,1H), 8.15 (d, J=1.8 Hz, 1H), 9.13 (d, J=8.7 Hz, 1H), 10.96 (s, 1H).

Examples 170 and 171

Examples 170 and 171 Step a

A solution of 2,4,6-trifluorobenzoic acid (2.00 g, 10.1 mmol), H₂SO₄ (3mL, 6 mmol) in EtOH (10 mL) was stirred for 12 hours at 80° C. It wasdiluted with water, extracted with EA (×3), washed with brine (×2). Theorganic layer was dried and concentrated to give 2.34 g (crude) ofdesired compound as yellow oil, which was used directly in the nextstep. ESI-MS m/z: need [M+H]⁺.

Examples 170 and 171 Step b

A solution of ethyl 2,4,6-trifluorobenzoate (2.34 g, 11.5 mmol),morpholine (999 mg, 11.5 mmol) and K₂CO₃ (2.76 g, 20.0 mmol) in DMF (10mL) was stirred for 12 hours at 100° C. It was diluted with water,extracted with EA (×3), washed with brine (×2). The organic layer wasdried and concentrated to give 2.31 g (crude) mixture of desiredcompound as yellow oil, which was used directly in the next step. ESI-MSm/z: 272.1 [M+H]⁺.

Examples 170 and 171 Step c

A solution of the compound from step b (2.31 g, 2.94 mmol) and NaOH (500mg) in MeOH (5 mL) and water (5 mL) was stirred for 5 hours. The crudeproduct was purified by reverse phase C18 column chromatography(MeCN/H₂O) to give desired compound as a white solid (1.79 g, 86%).ESI-MS m/z: 244.1 [M+H]⁺.

Examples 170 and 171 Step d

Examples 170 and 171 were prepared using a procedure similar to thatused to prepare Example 151 where 2,6-difluoro-4-morpholinobenzoic acidand 2,4-difluoro-6-morpholinobenzoic acid, respectively, were used inplace of 6-fluoro-2-morpholinonicotinic acid. Example 170: ESI-MS m/z:517.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ3.30 (m, 4H), 3.72 (m, 4H),5.15 (d, J=8.5 Hz, 1H), 6.85 (d, J=12.9 Hz, 2H), 7.25-7.38 (m, 3H),7.43-7.58 (m, 5H), 7.68 (ddd, J=8.4, 7.1, 1.7 Hz, 1H), 9.10 (d, J=8.5Hz, 1H), 10.99 (s, 1H). Example 171: ESI-MS m/z: 517.3 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆) δ 2.91 (t, J=4.6 Hz, 4H), 3.61 (q, J=3.9 Hz, 4H),5.16 (d, J=8.7 Hz, 1H), 6.75-7.12 (m, 2H), 7.21-7.42 (m, 3H), 7.42-7.61(m, 5H), 7.64-7.77 (m, 1H), 9.17 (d, J=8.8 Hz, 1H), 10.99 (s, 1H).

Example 172

Example 172 Step a

A solution of ethyl 2-chloro-4-morpholinopyrimidine-5-carboxylate,prepared similarly to the method described in Example 145 (0.54 g, 2mmol), 1H-pyrazole (0.27 g, 4 mmol) and Cs₂CO₃ (1.30 g, 4 mmol) in DMF(20 mL) was stirred for 1 hour at rt. It was diluted with water andextracted with EA (×3). The organic layer was concentrated to giveyellow solid (0.6 g, 99%). ESI-MS m/z: 304.1 [M+H]⁺.

Example 172 Step b

A solution of the compound from step a (0.6 g, 1.98 mmol), LiOH (71 mg,2.97 mmol), in THF (10 mL) and water (2 mL) were stirred at roomtemperature for 16 hours. The solvent was removed and the crude productwas purified by reverse phase C18 column chromatography (MeCN/H₂O) togive desired compound as a white solid (200 mg, 37%). ESI-MS m/z: 276.2[M+H]⁺.

Example 172 Step c

Example 172 was prepared using a procedure similar to that used toprepare Example 151 where4-morpholino-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxylic acid was used inplace of 6-fluoro-2-morpholinonicotinic acid. ESI-MS m/z: 549.5 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 3.53 (m, 4H), 3.69 (m, 4H), 5.16 (d, J=8.3Hz, 1H), 6.55-6.67 (m, 1H), 7.29 (m, 1H), 7.36 (m, 2H), 7.46-7.55 (m,5H), 7.63-7.73 (m, 1H), 7.86 (d, J=1.6 Hz, 1H), 8.57 (s, 1H), 8.68 (d,J=2.7 Hz, 1H), 9.19 (d, J=8.5 Hz, 1H), 11.01 (s, 1H).

Example 173

Example 173 was prepared using a procedure similar to that used toprepare Example 151 where4-morpholino-2-(1H-1,2,4-triazol-1-yl)pyrimidine-5-carboxylic acid,which was prepared similarly to4-morpholino-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxylic acid which wasdescribed in Example 172 step b, was used in place of6-fluoro-2-morpholinonicotinic acid. ESI-MS m/z: 550.4 [M+H]⁺. ¹H NMR(300 MHz, DMSO-d₆) δ 3.55 (m, 4H), 3.69 (d, J=4.7 Hz, 4H), 5.16 (d,J=3.8 Hz, 1H), 7.19-7.41 (m, 3H), 7.42-7.62 (m, 5H), 7.67 (m, 1H), 8.30(s, 1H), 8.61 (s, 1H), 9.19 (s, 1H), 9.49 (s, 1H), 10.91 (s, 1H).

Example 174

Example 174 Step a

A solution of methyl 5-bromo-2-chloronicotinate (5.0 g, 20.0 mmol) inmorpholine (20 mL) was stirred for 1 hour at 120° C. It was concentratedand purified by reverse phase C18 column chromatography (MeCN/H₂O) togive the desired compound as yellow solid (5.4 g, 90%). ESI-MS m/z:302.9 [M+H]⁺.

Example 174 Step b

A solution of the compound from step a (1.3 g, 4.3 mmol), LiOH (517 mg,21.6 mmol) in THF/H₂O (10 mL) (1/1) was stirred at rt overnight. Thesolution was adjusted pH value to 4 with 3N HCl and extracted with EA.The solution was concentrated and purified by reverse phase C18 columnchromatography (MeCN/H₂O) to give the desired product as off-white solid(1.1 g, 88%). ESI-MS m/z: 287.0 [M+H]⁺.

Example 174 Step c

A solution of the compound from step b (1.1 g, 3.83 mmol), tert-butylhydrazinecarboxylate (607 mg, 4.59 mmol), HATU (1.75 g, 4.60 mmol),DIPEA (1.48 g, 11.49 mmol) in DMF (20 mL) was stirred at rt for 1 hour.The solution was purified by reverse phase C18 column chromatography(MeCN/H₂O) to give the desired product as off-white solid (1.3 g, 85%).ESI-MS m/z: 403.2 [M+H]⁺.

Example 174 Step d

A solution of the compound from step c (1.3 g, 3.24 mmol), Zn(CN)₂ (752mg, 6.28 mmol), Pd(PPh₃)₄ (750 mg, 0.62 mmol) in DMF (20 mL) was stirredat 120° C. for 1 hour. The solution was purified by reverse phase C18column chromatography (MeCN/H₂O) to tert-butyl2-(5-cyano-2-morpholinonicotinoyl)hydrazine-1-carboxylate as off-whitesolid (1.0 g, 89%). ESI-MS m/z: 348.3 [M+H]⁺.

Example 174 Step e

Example 174 was prepared using a procedure similar to that used toprepare Example 151 tert-butyl2-(5-cyano-2-morpholinonicotinoyl)hydrazine-1-carboxylate was used inplace of tert-butyl2-(6-fluoro-2-morpholinonicotinoyl)hydrazine-1-carboxylate. ESI-MS m/z:507.4 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 3.30-3.40 (m, 4H), 3.65-3.67(m, 4H), 5.14-5.16 (d, J=6.0 Hz, 1H), 7.26-7.30 (m, 1H), 7.33-7.36 (m,2H), 7.44-7.55 (m, 5H), 7.65-7.69 (m, 1H), 8.25 (m, 1H), 8.69-8.70 (m,1H), 9.22-9.24 (d, J=8.0 Hz, 1H), 10.99 (s, 1H).

Example 175

Example 175 Step a

The methyl 5-bromo-2-chloronicotinate (1.2 g, 4.8 mmol) and potassiumcyclopropyl trifluoroborate (2.13 g, 14.4 mmol) was dissolved in AcOH(30 mL) and water (30 mL). TFA (0.36 mL, 4.8 mmol) was added. Themixture was stirred at rt for 20 minutes. Mn(OAc)₃.2H₂O (11.6 g, 43.2mmol) was added and the mixture was heated to 70° C. under N₂atmosphere. After 48 hours the mixture was cooled to rt and saturatedNa₂CO₃ solution was added and then solid was filtered out. The filtratewas extracted with EA (200 mL×3). The combined organic phase was driedover anhydrous Na₂SO₄ and concentrated. The residue was purified bysilica gel chromatography (PE:EA=100:1 to 50:1) to give the desiredproduct as white solid (269 mg,) and the starting material (696 mg).ESI-MS m/z: 292.0 [M+H]⁺.

Example 175 Step b

The compound from step a (269 mg, 0.92 mmol) was dissolved in morpholine(3 mL) and it was heated to 100° C. for 1 hour. Water was added (10 mL)and the mixture was extracted with EA (20 mL×3) and the combined organicphase was dried and concentrated to give the desired product as a yellowoil (400 mg,). ESI-MS m/z: 343.1 [M+H]⁺.

Example 175 Step c

The compound from step b (400 mg, 1.17 mmol) was dissolved in THF (3 mL)and water (1 mL). LiOH (56 mg, 2.34 mmol) was added and the mixture washeated to 50° C. overnight. The mixture was cooled to rt and 6M HClsolution was added to adjust the pH to 3 and then concentrated. Theresidue was purified by reverse phase C18 column chromatography(MeCN/H₂O) to give the desired product as a yellow solid (300 mg, 78%).ESI-MS m/z: 327.0 [M+H]⁺.

Example 175 Step d

The compound from step c (300 mg, 0.92 mmol) was dissolved in DMF (5 mL)and BocNHNH₂ (242 mg, 1.83 mmol) was added. HATU (697 mg, 1.83 mmol) andDIPEA (0.3 mL) was added. The mixture was stirred at rt for 2 hours.Water (10 mL) was added and the mixture was extracted with EA (15 mL×3).The combined organic phase was dried over anhydrous Na₂SO₄ andconcentrated. The residue was purified by gel chromatography (PE/EA=3/1)to give the desired product as a yellow solid (350 mg, 86%). ESI-MS m/z:441.0 [M+H]⁺.

Example 175 Step e

To a stirred solution of the compound from step 4 (350 mg, 0.79 mmol)and Zn(CN)₂ (183 mg, 1.58 mmol) in DMF (5 mL) was added Pd(PPh₃)₄(183.28 mg, 0.158 mmol). The mixture was heated to 120° C. for 1 hourunder N₂ atmosphere. Then it was cooled to rt, Sat. FeSO₄ solution wasadded and the mixture was extracted with EA (50 mL×3). The combinedorganic phase was washed with water, brine and dried over anhydrousNa₂SO₄ and concentrated. The residue was purified by silicagelchromatography to give the desired compound as a yellow solid (290 mg,95%). ESI-MS m/z: 388.4 [M+H]⁺.

Example 175 Step f

Example 175 was prepared using a procedure similar to that used toprepare Example 151 tert-butyl2-(5-cyano-6-cyclopropyl-2-morpholinonicotinoyl)hydrazine-1-carboxylatewas used in place of tert-butyl2-(6-fluoro-2-morpholinonicotinoyl)hydrazine-1-carboxylate. ESI-MS m/z:547.2 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 0.95-1.23 (m, 4H), 2.24-2.48(m, 1H), 3.18-3.43 (m, 4H), 3.64 (t, J=4.8 Hz, 4H), 5.15 (d, J=8.2 Hz,1H), 7.22-7.61 (m, 8H), 7.68 (ddd, J=8.5, 7.0, 1.8 Hz, 1H), 8.12 (s,1H), 9.17 (d, J=8.5 Hz, 1H), 10.98 (s, 1H).

Example 176

Example 176 was prepared using a procedure similar to that used toprepare Example 151 tert-butyl2-(5-cyano-6-ethyl-2-morpholinonicotinoyl)hydrazine-1-carboxylate, whichwas prepared similarly to tert-butyl2-(5-cyano-6-cyclopropyl-2-morpholinonicotinoyl)hydrazine-1-carboxylateas described in Example 175 step e, was used in place of tert-butyl2-(6-fluoro-2-morpholinonicotinoyl)hydrazine-1-carboxylate. ESI-MS m/z:535.1 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 1.23 (m, 3H), 2.84 (m, 2H),3.36 (m, 4H), 3.65 (m, 4H), 5.12 (d, J=8.3 Hz, 1H), 7.20-7.39 (m, 3H),7.40-7.59 (m, 5H), 7.65 (m, 1H), 8.14 (s, 1H), 9.17 (d, J=8.5 Hz, 1H),10.98 (s, 1H).

Example 177

Example 177 Step a

A solution of the compound ethyl5-amino-1-methyl-1H-pyrazole-4-carboxylate (1.69 g, 10 mmol),1-bromo-2-(2-bromoethoxy) ethane (3.45 g, 15 mmol) and Cs₂CO₃ (9.77 g,30 mmol) in DMA (30 mL) was stirred overnight at 120° C. The crudeproduct was purified by reverse phase C18 column chromatography(MeCN/H₂O) to give desired compound 700 mg (crude). ESI-MS m/z: 240.1[M+H]⁺.

Example 177 Step b

Example 177 was prepared using a procedure similar to that used toprepare Example 152 where methyl1-methyl-5-morpholino-1H-pyrazole-4-carboxylate was used in place ofethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI-MS m/z: 485.4[M+H]⁺. ¹H NMR (400 MHz, Methanol-d₄) δ 3.19 (dd, J=5.7, 3.5 Hz, 4H),3.83 (d, J=6.5 Hz, 7H), 5.29 (s, 1H), 7.26-7.39 (m, 2H), 7.39-7.48 (m,3H), 7.49-7.59 (m, 3H), 7.64-7.69 (m, 1H), 7.83 (s, 1H).

Example 178

Example 178 Step a

A solution of 1-methyl-4-nitro-1H-pyrazole-5-carboxylic acid (1.03 g, 6mmol), EtBr (3 mL) and K₂CO₃ (1.66 g, 12 mmol) in DMF (30 mL) wasstirred for 1 hour at 60° C. Then it was poured into water and extractedwith EA (3×) to give desired compound as a light yellow solid. (995 mg,83%). ESI-MS m/z: 200.2 [M+H]⁺.

Example 178 Step b

A solution of compound from step a (995 mg, 5 mmol) and Pd/C (200 mg) inEtOH (50 mL) was stirred for 3 hours at 25° C. Pd/C was filtered out andthe filtrate was concentrated to give desired compound as a light brownsolid. (845 mg, 100%). ESI-MS m/z: 170.2 [M+H]⁺.

Example 178 Step c

A solution of compound from step b (845 mg, 5 mmol),1-bromo-2-(2-bromoethoxy)ethane (2.3 g, 10 mmol), NaI (1.5 g, 10 mmol)and K₂CO₃ (2.8 g, 20 mmol) in DMA (50 mL) was stirred for 3 hours at120° C. The solvent was removed and the residue was purified by reversephase C18 column chromatography (MeCN/H₂O) to give desired compound asbrown oil. (720 mg, 60%). ESI-MS m/z: 240.2 [M+H]⁺.

Example 178 Step d

Example 178 was prepared using a procedure similar to that used toprepare Example 152 where ethyl1-methyl-4-morpholino-1H-pyrazole-5-carboxylate was used in place ofethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI-MS m/z: 485.4[M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 2.84-2.93 (m, 4H), 3.64 (m, 4H),3.98 (s, 3H), 5.16 (d, J=8.3 Hz, 1H), 7.24-7.62 (m, 9H), 7.63-7.75 (m,1H), 9.26 (d, J=8.4 Hz, 1H), 11.01 (s, 1H).

Example 179

Example 179 Step a

A solution of ethyl 3-aminobenzofuran-2-carboxylate (1.03 g, 5 mmol) andNaH (480 mg, 12 mmol) in DMF (30 mL) was stirred for 0.5 hour at 0° C.Then 1-bromo-2-(2-bromoethoxy)ethane (1.38 g, 6 mmol) was added to themixture and stirred for 1 hr at rt H₂O (50 mL) was added and it wasextracted with EA (3×). The organic layer was concentrated and purifiedby reverse phase C18 column chromatography (MeCN/H₂O) to give desiredcompound as light brown oil. (530 mg, 40%). ESI-MS m/z: 276.2 [M+H]⁺.

Example 179 Step b

Example 179 was prepared using a procedure similar to that used toprepare Example 152 where ethyl 3-morpholinobenzofuran-2-carboxylate wasused in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI-MSm/z: 521.4 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 3.32 (m, 4H), 3.74 (m,4H), 5.17 (d, J=8.4 Hz, 1H), 7.22-7.75 (m, 12H), 7.86-8.00 (m, 1H), 9.31(d, J=8.5 Hz, 1H), 11.00 (s, 1H).

Example 180

Example 180 Step a

A solution of ethyl 3-aminothieno[2,3-b]pyridine-2-carboxylate (500 mg,2.25 mmol), 1-bromo-2-(2-bromoethoxy)ethane (1.38 g, 6 mmol) and Cs₂CO₃(1.63 g, 5 mmol) in DMA (30 mL) was stirred for 3 hours at 80° C. H₂O(50 mL) was added and it was extracted with EA (3×). The organic layerwas concentrated and purified by reverse phase C18 column chromatography(MeCN/H₂O) to give desired compound as light brown oil. (500 mg, 76%).ESI-MS m/z: 293.2 [M+H]⁺.

Example 180 Step b

Example 180 was prepared using a procedure similar to that used toprepare Example 152 where ethyl3-morpholinothieno[2,3-b]pyridine-2-carboxylate was used in place ofethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI-MS m/z: 538.4[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 3.30-3.17 (m, 4H), 3.77 (d, J=6.8Hz, 4H), 5.19 (d, J=8.2 Hz, 1H), 7.29 (t, J=7.7 Hz, 1H), 7.37 (d, J=8.0Hz, 2H), 7.61-7.42 (m, 6H), 7.68 (t, J=7.6 Hz, 1H), 8.34 (d, J=8.1 Hz,1H), 8.66 (d, J=4.6 Hz, 1H), 9.40 (d, J=8.1 Hz, 1H), 11.03 (s, 1H).

Example 181

Example 181 Step a

A solution of the ethyl 3-amino-1-methyl-1H-pyrazole-4-carboxylate (500mg, 2.95 mmol), Cs₂CO₃ (2.9 g, 8.87 mmol), 1-bromo-2-(2-bromoethoxy)ethane (1.37 g, 5.90 mmol) in DMA (10 mL) as stirred at 120° C.overnight. Then H₂O (20 mL) was added to the mixture and it wasextracted with EA (×3). The organic layer was dried and purified byflash to give desired compound as yellow oil (610 mg, 87%). ESI-MS m/z:240.0 [M+H]⁺.

Example 181 Step b

Example 181 was prepared using a procedure similar to that used toprepare Example 152 where ethyl1-methyl-3-morpholino-1H-pyrazole-4-carboxylate was used in place ofethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI-MS m/z: 485.4[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 3.14-3.15 (m, 4H), 3.65-3.67 (m,4H), 3.77 (s, 3H), 5.07-5.09 (d, J=8.0 Hz, 1H), 7.32-7.35 (m, 3H),7.45-7.51 (m, 6H), 8.04 (s, 1H), 8.90-8.93 (m, 1H), 10.86-11.07 (m, 1H).

Example 182

Example 182 Step a

A solution of the methyl 3-amino-5-bromothiophene-2-carboxylate (880 mg,3.72 mmol), Cs₂CO₃ (3.64 g, 11.16 mmol), 1-bromo-2-(2-bromoethoxy)ethane (1.73 g, 7.45 mmol) in DMA (10 mL) as stirred at 80° C.overnight. Then H₂O (20 ml) was added to the mixture and it wasextracted with EA (×3). The organic layer was dried and purified byreverse phase C18 column chromatography (MeCN/H₂O) to give desiredcompound as yellow oil (540 mg, 48%). ESI-MS m/z: 307.9 [M+H]⁺.

Example 182 Step b

Example 182 was prepared using a procedure similar to that used toprepare Example 152 where methyl5-bromo-3-morpholinothiophene-2-carboxylate was used in place of ethyl2-morpholino-4-(trifluoromethyl)benzoate. ESI-MS m/z: 566.9 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 3.06-3.07 (m, 4H), 3.64-3.70 (m, 4H), 5.09-5.11(d, J=8.0 Hz, 1H), 7.24-7.29 (m, 2H), 7.33-7.35 (m, 2H), 7.41-7.49 (m,5H), 7.51-7.68 (m, 1H), 9.11-9.13 (m, 1H), 10.94-10.99 (m, 1H).

Example 183

Example 183 was prepared using a procedure similar to that used toprepare Example 20 where 5-cyanothiophene-2-carboxylic acid was used inplace of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 427.1 [M+H]⁺.

Example 184

Example 184 was prepared using a procedure similar to that used toprepare Example 20 where 4-(pyrrolidin-1-yl)benzoic acid was used inplace of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 465.4 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 1.98 (q, J=4.7, 3.1 Hz, 4H), 3.35 (q, J=4.7,3.1 Hz, 4H), 5.13 (d, J=8.7 Hz, 1H), 6.32-6.78 (m, 2H), 7.22-7.42 (m,3H), 7.42-7.59 (m, 5H), 7.58-7.77 (m, 3H), 8.85 (d, J=8.7 Hz, 1H), 10.98(s, 1H).

Example 185

Example 185 was prepared using a procedure similar to that used toprepare Example 20 where 3-fluoro-5-methoxypicolinic acid was used inplace of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 455.1 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 3.93 (s, 3H), 5.17 (d, J=8.5 Hz, 1H), 7.22-7.39(m, 3H), 7.40-7.58 (m, 5H), 7.60-7.72 (m, 2H), 8.32 (m, 1H), 9.26 (d,J=8.5 Hz, 1H), 11.00 (s, 1H).

Example 186

Example 186 was prepared using a procedure similar to that used toprepare Example 20 where 4-(2-methyl-2H-tetrazol-5-yl)benzoic acid wasused in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 478.2[M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 4.45 (s, 3H), 5.18 (d, J=8.3 Hz,1H), 7.24-7.40 (m, 3H), 7.41-7.59 (m, 5H), 7.63-7.73 (m, 1H), 8.00 (d,J=8.4 Hz, 2H), 8.23 (d, J=8.4 Hz, 2H), 9.27 (d, J=8.5 Hz, 1H), 11.02 (s,1H).

Example 187

Example 187 was prepared using a procedure similar to that used toprepare Example 20 where 2-methylbenzo[d]thiazole-6-carboxylic acid wasused in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 467.3[M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 11.02 (s, 1H), 9.17 (s, 1H), 8.53(d, J=1.7 Hz, 1H), 8.04 (d, J=8.5 Hz, 1H), 7.91 (dd, J=8.6, 1.8 Hz, 1H),7.66 (ddd, J=8.4, 7.2, 1.7 Hz, 1H), 7.59-7.40 (m, 5H), 7.39-7.20 (m,3H), 5.16 (s, 1H), 2.83 (s, 3H).

Example 188

Example 188 was prepared using a procedure similar to that used toprepare Example 20 where isobutyric acid was used in place of5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 362.3 [M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 1.23 (d, J=6.9 Hz, 6H), 3.02 (hept, J=6.9 Hz, 1H), 5.04(d, J=8.7 Hz, 1H), 7.19-7.41 (m, 3H), 7.38-7.58 (m, 5H), 7.65 (ddd,J=8.4, 7.0, 1.8 Hz, 1H), 8.71 (d, J=8.7 Hz, 1H), 10.93 (s, 1H).

Example 189

Example 189 was prepared using a procedure similar to that used toprepare Example 20 where pivalic acid was used in place of5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 376.2 [M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 1.29 (s, 9H), 5.03 (d, J=8.6 Hz, 1H), 7.19-7.37 (m, 3H),7.39-7.58 (m, 5H), 7.65 (ddd, J=8.4, 7.0, 1.8 Hz, 1H), 8.68 (d, J=8.6Hz, 1H), 10.93 (s, 1H).

Example 190

Example 190 was prepared using a procedure similar to that used toprepare Example 20 where butyric acid was used in place of5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 362.2 [M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 0.92 (t, J=7.4 Hz, 3H), 1.64 (h, J=7.4 Hz, 2H), 2.64 (t,J=7.3 Hz, 2H), 5.03 (d, J=8.3 Hz, 1H), 7.19-7.58 (m, 8H), 7.65 (ddd,J=8.4, 7.0, 1.8 Hz, 1H), 8.72 (d, J=8.5 Hz, 1H), 10.94 (s, 1H).

Example 191

Example 191 was prepared using a procedure similar to that used toprepare Example 20 where 2-methoxyacetic acid was used in place of5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 364.1 [M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 3.29 (s, 3H), 4.45 (s, 2H), 5.08 (d, J=8.6 Hz, 1H),7.20-7.38 (m, 3H), 7.38-7.59 (m, 5H), 7.63-7.68 (m, 1H), 9.01 (d, J=8.6Hz, 1H), 10.96 (s, 1H).

Example 192

Example 192 was prepared using a procedure similar to that used toprepare Example 20 where 4,4,4-trifluorobutanoic acid was used in placeof 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 416.1 [M+H]⁺. ¹H NMR(300 MHz, DMSO-d₆) δ 2.58-2.81 (m, 2H), 2.98 (dd, J=8.7, 6.5 Hz, 2H),5.05 (d, J=8.6 Hz, 1H), 7.19-7.38 (m, 3H), 7.38-7.60 (m, 5H), 7.63-7.68(m, 1H), 8.85 (d, J=8.7 Hz, 1H), 10.95 (s, 1H).

Example 193

Example 193 was prepared using a procedure similar to that used toprepare Example 20 where 3-cyanopropanoic acid was used in place of5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 373.1 [M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 2.89 (t, J=6.8 Hz, 2H), 3.07 (t, J=7.2 Hz, 2H), 5.04 (s,1H), 7.18-7.37 (m, 3H), 7.38-7.58 (m, 5H), 7.62-7.67 (m, 1H), 8.88 (d,J=4.9 Hz, 1H), 10.94 (s, 1H).

Example 194

Example 194 was prepared using a procedure similar to that used toprepare Example 20 where 2-(methylsulfonyl)acetic acid was used in placeof 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 412.1 [M+H]⁺. ¹H NMR(300 MHz, DMSO-d₆) δ 3.13 (s, 3H), 4.89 (s, 2H), 5.09 (d, J=8.5 Hz, 1H),7.20-7.40 (m, 3H), 7.38-7.59 (m, 5H), 7.63-7.68 (m, 1H), 9.17 (d, J=8.5Hz, 1H), 10.97 (s, 1H).

Example 195

Example 195 was prepared using a procedure similar to that used toprepare Example 20 where 1-methylcyclopropane-1-carboxylic acid was usedin place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 374.2 [M+H]⁺.¹H NMR (300 MHz, DMSO-d₆) δ 0.77-0.92 (m, 2H), 1.00-1.10 (m, 2H), 1.39(s, 3H), 5.00 (d, J=7.8 Hz, 1H), 7.18-7.58 (m, 8H), 7.61-7.67 (m, 1H),8.62 (d, J=8.1 Hz, 1H), 10.94 (s, 1H).

Example 196

Example 196 was prepared using a procedure similar to that used toprepare Example 20 where cyclobutanecarboxylic acid was used in place of5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 374.3 [M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 1.79-2.12 (m, 2H), 2.13-2.39 (m, 4H), 3.58 (m, 1H), 5.05(d, J=8.7 Hz, 1H), 7.19-7.58 (m, 8H), 7.65 (m, 1H), 8.75 (d, J=8.7 Hz,1H), 10.94 (s, 1H).

Example 197

Example 197 was prepared using a procedure similar to that used toprepare Example 20 where cyclopentanecarboxylic acid was used in placeof 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 388.3 [M+H]⁺. ¹H NMR(300 MHz, DMSO-d₆) δ 1.52-1.83 (m, 6H), 1.87-2.07 (m, 2H), 3.08-3.25 (m,1H), 5.03 (d, J=8.6 Hz, 1H), 7.19-7.37 (m, 3H), 7.38-7.58 (m, 5H), 7.65(m, 1H), 8.69 (d, J=8.7 Hz, 1H), 10.93 (s, 1H).

Example 198

Example 198 was prepared using a procedure similar to that used toprepare Example 20 where (R)-tetrahydrofuran-2-carboxylic acid was usedin place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 390.3 [M+H]⁺.¹H NMR (300 MHz, DMSO-d₆) δ 1.82-2.30 (m, 4H), 3.74-3.86 (m, 2H), 4.94(m, 1H), 5.06 (d, J=8.5 Hz, 1H), 7.18-7.38 (m, 3H), 7.38-7.71 (m, 6H),8.93 (m, 1H), 10.96 (s, 1H).

Example 199

Example 199 was prepared using a procedure similar to that used toprepare Example 20 where 3-phenylpropanoic acid was used in place of5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 424.4 [M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 2.90-3.09 (m, 4H), 5.02 (s, 1H), 7.14-7.71 (m, 14H),8.73 (s, 1H), 10.95 (s, 1H).

Example 200

Example 200 was prepared using a procedure similar to that used toprepare Example 20 where 5-cyano-6-methylpicolinic acid was used inplace of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 436.3 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 2.73 (s, 3H), 5.20 (d, J=7.2 Hz, 1H), 7.21-7.40(m, 3H), 7.40-7.59 (m, 5H), 7.67 (ddd, J=8.5, 7.2, 1.8 Hz, 1H), 7.96 (d,J=8.2 Hz, 1H), 8.38 (d, J=8.2 Hz, 1H), 9.52 (d, J=8.2 Hz, 1H), 11.01 (s,1H).

Example 201

A solution of Example 7 (0.2 g, 0.48 mmol), K₂CO₃ (0.13 g, 0.96 mmol)MeI (68 mg, 0.48 mmol) in DMF (3 mL). The mixture was stirred at r.t.for 6 hrs, It was diluted with EA and washed with brine. The organicphase was dried and concentrated. The residue was purified by Prep-HPLCto give the desired product as a white solid (31.2 mg, 15.2%). ESI-MSm/z: 428.1 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 3.44 (s, 3H), 5.23 (d,J=8.6 Hz, 1H), 7.36-7.62 (m, 9H), 7.77 (m, 2H), 7.83-7.96 (m, 2H), 9.22(d, J=8.7 Hz, 1H).

Example 202

Example 202 was prepared using a procedure similar to that used toprepare Example 20 where 4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)benzoicacid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z:530.4 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 5.19 (d, J=8.4 Hz, 1H),7.19-7.59 (m, 9H), 7.61-7.76 (m, 3H), 7.94-8.06 (m, 3H), 9.29 (d, J=8.5Hz, 1H), 11.01 (s, 1H).

Example 203

Example 203 was prepared using a procedure similar to that used toprepare Example 20 where 3,3,3-trifluoropropanoic acid was used in placeof 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 402.1 [M+H]⁺. ¹H NMR(300 MHz, DMSO-d₆) δ 4.11 (q, J=10.7 Hz, 2H), 5.07 (d, J=8.4 Hz, 1H),7.20-7.59 (m, 8H), 7.65 (ddd, J=8.4, 7.0, 1.8 Hz, 1H), 9.13 (d, J=8.5Hz, 1H), 10.96 (s, 1H).

Example 204

Example 204 was prepared using a procedure similar to that used toprepare Example 20 where 1-fluorocyclopropane-1-carboxylic acid was usedin place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 370.3 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 1.19-1.34 (m, 2H), 1.49-1.63 (m, 2H), 5.10(d, J=8.4 Hz, 1H), 7.23-7.39 (m, 3H), 7.42-7.62 (m, 6H), 7.67 (m, 1H),9.18 (d, J=8.5 Hz, 1H), 10.99 (s, 1H).

Example 205

Example 205 was prepared using a procedure similar to that used toprepare Example 20 where (S)-2,2-dimethylcyclopropane-1-carboxylic acidwas used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 388.2[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 0.94-1.00 (m, 5H), 1.18 (s, 3H),1.86-1.90 (m, 1H), 5.03-5.05 (d, J=8.0 Hz, 1H), 7.24-7.34 (m, 3H),7.44-7.55 (m, 5H), 7.64-7.68 (m, 1H), 8.70-8.73 (m, 1H), 10.93 (s, 1H).

Example 206

Example 206 was prepared using a procedure similar to that used toprepare Example 20 where 3,3-dimethylcyclobutane-1-carboxylic acid wasused in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 402.4[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 1.10 (s, 3H), 1.20 (s, 3H),1.99-2.16 (m, 4H), 3.56 (m, 1H), 5.06 (d, J=8.7 Hz, 1H), 7.22-7.38 (m,3H), 7.41-7.58 (m, 5H), 7.66 (m, 1H), 8.75 (d, J=8.7 Hz, 1H), 10.95 (s,1H).

Example 207

Example 207 was prepared using a procedure similar to that used toprepare Example 20 where (S)-tetrahydrofuran-2-carboxylic acid was usedin place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 390.2 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 1.93-2.01 (m, 2H), 2.15-2.22 (m, 2H),3.79-3.83 (m, 2H), 4.93-5.08 (m, 2H), 7.25-7.35 (m, 3H), 7.44-7.53 (m,5H), 7.64-7.68 (m, 1H), 8.93-8.96 (m, 1H), 11.00 (s, 1H).

Example 208

Example 208 was prepared using a procedure similar to that used toprepare Example 20 where 2,2-dimethyl-3-phenylpropanoic acid was used inplace of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 452.4 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 1.22-1.30 (m, 6H), 2.91 (s, 2H), 5.05 (d, J=8.7Hz, 1H), 6.95-7.02 (m, 2H), 7.15-7.38 (m, 6H), 7.42-7.60 (m, 5H), 7.67(m, 1H), 8.73 (d, J=8.8 Hz, 1H), 10.96 (s, 1H).

Example 209

Example 209 Step a

A solution of3-amino-1-(4-methoxybenzyl)-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one,from Example 91 step b, (0.37 g, 1 mmol), TCDI (196 mg, 1.1 mmol) in DMF(10 mL) was stirred for 0.5 hours. 4-fluorobenzohydrazide (169 mg, 1.1mmol) was added and then stirred for 3 hours. EDCI (764 mg, 4 mmol) wasadded and then stirred for 1 hours at 60° C. Then it was purified byflash to afford product as a white solid (0.3 g, 56%). ESI-MS m/z: 534.3[M+H]⁺.

Example 209 Step b

A solution of the compound from step a (0.3 g, 0.56 mmol), K₂CO₃ (0.15g, 1.12 mmol) MeI (95 mg, 0.68 mmol) in DMF (5 mL). The mixture wasstirred at r.t. for 6 hrs, It was diluted with EA and washed with brine.The organic phase was dried and concentrated to afford product as ayellow solid (0.3 g, 98%). ESI-MS m/z: 548.5 [M+H]⁺.

Example 209 Step c

A mixture of the compound from step b (200 mg, 0.37 mmol) and AlCl₃ (490mg, 3.7 mmol) in anisole (5 mL) was heated to 70° C. for 3 hrs under N₂.Solvent was removed. The residue was purified by Prep-HPLC to affordproduct as light yellow solid (79.6 mg, 50.4%). ESI-MS m/z: 428.1[M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 3.55 (s, 3H), 5.49 (s, 1H),7.25-7.45 (m, 5H), 7.46-7.64 (m, 5H), 7.65-7.77 (m, 1H), 7.93 (m, 2H),11.06 (s, 1H).

Example 210

Example 210 was prepared using a procedure similar to that used toprepare Example 20 where 4-(4-methylpiperazin-1-yl)benzoic acid was usedin place of 5-chlorofuran-2-carboxylic acid ESI-MS m/z: 494.3 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 3.15 (t, J=4.9 Hz, 4H), 3.75 (dd, J=6.0, 3.6Hz, 4H), 5.10-5.19 (m, 1H), 7.08-7.73 (m, 14H), 7.82 (s, 1H), 8.99-9.09(m, 1H), 10.99 (s, 1H).

Example 211

Example 211 was prepared using a procedure similar to that used toprepare Example 20 where 6-(1H-pyrazol-1-yl)nicotinic acid was used inplace of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 482.3 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 5.18 (d, J=6.6 Hz, 1H), 6.64 (dd, J=2.7, 1.7Hz, 1H), 7.22-7.59 (m, 8H), 7.67 (ddd, J=8.4, 7.1, 1.7 Hz, 1H), 7.90(dd, J=1.6, 0.7 Hz, 1H), 8.09 (dd, J=8.6, 0.9 Hz, 1H), 8.36 (dd, J=8.7,2.3 Hz, 1H), 8.68 (dd, J=2.6, 0.7 Hz, 1H), 8.86 (dd, J=2.3, 0.8 Hz, 1H),9.28 (d, J=7.2 Hz, 1H), 11.01 (s, 1H).

Example 212

Example 212 was prepared using a procedure similar to that used toprepare Example 20 where 3-(1H-imidazol-1-yl)benzoic acid was used inplace of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 462.1 [M+H]⁺. HNMR (300 MHz, DMSO-d₆) δ 5.21 (d, J=8.4 Hz, 1H), 7.13-7.20 (m, 1H),7.24-7.61 (m, 8H), 7.63-7.90 (m, 5H), 7.98-8.11 (m, 1H), 8.37 (s, 1H),9.23 (d, J=8.3 Hz, 1H), 11.02 (s, 1H).

Example 213

Example 213 was prepared using a procedure similar to that used toprepare Example 20 where 4-(1H-imidazol-1-yl)benzoic acid was used inplace of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 378.1 [M+H]⁺. HNMR (300 MHz, DMSO-d₆) δ 1.49 (s, 6H), 2.44 (s, 1H), 5.07 (d, J=8.6 Hz,1H), 5.67 (s, 1H), 7.22-7.43 (m, 3H), 7.41-7.61 (m, 5H), 7.67 (m, 1H),8.82 (d, J=8.7 Hz, 1H), 10.92-10.99 (s, 1H).

Example 214

Example 214 was prepared using a procedure similar to that used toprepare Example 20 where 3,3-difluorocyclobutane-1-carboxylic acid wasused in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 410.1[M+H]⁺. H-NMR-PH-ETA-A1-426-0: ¹H NMR (300 MHz, DMSO-d₆) δ 2.75-3.17 (m,4H), 3.55 (dddd, J=11.1, 9.3, 5.3, 3.8 Hz, 1H), 5.06 (d, J=8.6 Hz, 1H),7.20-7.38 (m, 3H), 7.38-7.59 (m, 5H), 7.65 (ddd, J=8.5, 7.0, 1.8 Hz,1H), 8.89 (d, J=8.6 Hz, 1H), 10.95 (s, 1H).

Example 215

Example 215 was prepared using a procedure similar to that used toprepare Example 20 where tetrahydrofuran-3-carboxylic acid was used inplace of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 390.1 [M+H]⁺. HNMR (300 MHz, DMSO-d₆) δ 2.03-2.31 (m, 2H), 3.60 (m, 1H), 3.70-3.91 (m,3H), 3.97 (m, 1H), 5.07 (d, J=8.7 Hz, 1H), 7.22-7.40 (m, 3H), 7.41-7.61(m, 5H), 7.67 (m, 1H), 8.51 (s, 0.2H), 8.83 (d, J=8.6 Hz, 1H), 10.97 (d,J=8.6 Hz, 1H).

Example 216

Example 216 was prepared using a procedure similar to that used toprepare Example 20 where 3-fluoro-4-(1H-1,2,4-triazol-1-yl)benzoic acidwas used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 481.3[M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 5.19 (d, J=7.5 Hz, 1H), 7.22-7.59(m, 8H), 7.67 (ddd, J=8.5, 7.0, 1.7 Hz, 1H), 7.78-7.94 (m, 2H), 8.03 (t,J=8.0 Hz, 1H), 8.36 (s, 1H), 9.11 (d, J=2.5 Hz, 1H), 9.32 (d, J=8.2 Hz,1H), 11.02 (s, 1H).

Example 217

Example 217 was prepared using a procedure similar to that used toprepare Example 20 where 3-methyl-4-(1H-1,2,4-triazol-1-yl)benzoic acidwas used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 477.3[M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 2.30 (s, 3H), 5.19 (d, J=8.1 Hz,1H), 7.22-7.74 (m, 10H), 7.80 (dd, J=8.4, 1.9 Hz, 1H), 7.91 (t, J=1.2Hz, 1H), 8.28 (s, 1H), 8.97 (s, 1H), 9.23 (d, J=8.2 Hz, 1H), 11.01 (s,1H).

Example 218

Example 218 was prepared using a procedure similar to that used toprepare Example 20 where 2-methyl-4-(1H-1,2,4-triazol-1-yl)benzoic acidwas used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 477.2[M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 2.67 (s, 3H), 5.20 (d, J=7.9 Hz,1H), 7.24-7.43 (m, 3H), 7.44-7.64 (m, 5H), 7.64-7.78 (m, 1H), 7.95 (d,J=16.1 Hz, 3H), 8.31 (s, 1H), 9.19 (d, J=8.3 Hz, 1H), 9.41 (s, 1H),11.01 (s, 1H).

Example 219

Example 219 was prepared using a procedure similar to that used toprepare Example 20 where 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzoicacid was used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z:506.2 [M+H]⁺. H NMR (300 MHz, DMSO-d₆) δ 2.18 (s, 3H), 3.94 (s, 3H),5.19 (d, J=7.9 Hz, 1H), 7.19-7.81 (m, 13H), 7.89 (d, J=1.4 Hz, 1H), 9.19(d, J=8.1 Hz, 1H), 11.03 (s, 1H).

Example 220

Example 220 was prepared using a procedure similar to that used toprepare Example 20 where 4-((tetrahydro-2H-pyran-4-yl)oxy)benzoic acidwas used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 496.4[M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 1.62 (dtd, J=13.3, 9.0, 4.1 Hz, 2H),1.91-2.09 (m, 2H), 3.51 (ddd, J=11.7, 9.5, 2.8 Hz, 2H), 3.88 (dt,J=11.4, 4.6 Hz, 2H), 4.70 (td, J=8.9, 4.5 Hz, 1H), 5.16 (d, J=8.5 Hz,1H), 7.16 (d, J=8.8 Hz, 2H), 7.24-7.43 (m, 3H), 7.42-7.62 (m, 5H),7.63-7.84 (m, 3H), 9.02 (d, J=8.5 Hz, 1H), 10.98 (s, 1H).

Example 221

Example 221 was prepared using a procedure similar to that used toprepare Example 20 where pyrrolidine-3-carboxylic acid was used in placeof 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 489.1 [M+H]⁺. ¹H NMR(300 MHz, DMSO-d₆) δ 1.98 (dt, J=12.8, 7.0 Hz, 1H), 2.12 (ddd, J=12.9,8.7, 6.4 Hz, 1H), 2.99 (q, J=8.2, 6.8 Hz, 3H), 3.27 (dd, J=11.1, 7.8 Hz,1H), 3.43 (q, J=7.7 Hz, 1H), 5.04-5.10 (m, 1H), 7.24-7.39 (m, 3H),7.43-7.59 (m, 5H), 7.67 (ddd, J=8.4, 7.0, 1.8 Hz, 1H), 8.34 (s, 2H),8.80 (d, J=8.4 Hz, 1H).

Example 222

Example 222 was prepared using a procedure similar to that used toprepare Example 20 where 7-azaspiro[3.5]nonane-2-carboxylic acid wasused in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 443.4[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 1.63 (q, J=5.1 Hz, 2H), 1.75 (dd,J=7.2, 3.9 Hz, 2H), 2.03 (ddd, J=12.6, 8.3, 2.2 Hz, 2H), 2.18-2.29 (m,2H), 2.86 (dt, J=34.9, 5.5 Hz, 4H), 3.59 (d, J=8.6 Hz, 1H), 5.05 (d,J=7.8 Hz, 1H), 7.22-7.40 (m, 3H), 7.42-7.59 (m, 5H), 7.66 (ddd, J=8.5,7.1, 1.7 Hz, 1H), 8.40 (s, 1H), 8.77 (d, J=8.7 Hz, 1H).

Example 223

Example 223 was prepared using a procedure similar to that used toprepare Example 20 where 3-methylpyrrolidine-3-carboxylic acid was usedin place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 403.3 [M+H]⁺. HNMR (300 MHz, DMSO-d₆) δ 1.40 (s, 3H), 1.80 (m, 1H), 2.24 (m, 1H), 2.88(d, J=11.2 Hz, 1H), 2.94-3.16 (m, 3H), 3.23 (d, J=11.2 Hz, 1H), 5.07 (d,J=8.4 Hz, 1H), 7.22-7.40 (m, 3H), 7.41-7.61 (m, 5H), 7.61-7.73 (m, 1H),8.41 (s, 1H), 8.78 (d, J=8.7 Hz, 1H), 11.10 (s, 1H).

Example 224

Example 224 was prepared using a procedure similar to that used toprepare Example 20 where 2-(4-methylpiperazin-1-yl)benzoic acid was usedin place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 494.4 [M+H]⁺.¹H NMR (300 MHz, DMSO-d₆) δ 2.18 (s, 3H), 2.38 (d, J=5.4 Hz, 4H), 2.89(t, J=4.6 Hz, 4H), 5.18 (d, J=8.5 Hz, 1H), 7.06-7.22 (m, 2H), 7.23-7.41(m, 3H), 7.41-7.59 (m, 6H), 7.59-7.75 (m, 2H), 9.03 (d, J=8.6 Hz, 1H),10.99 (s, 1H).

Example 225

Example 225 was prepared using a procedure similar to that used toprepare Example 20 where 6-(1H-1,2,4-triazol-1-yl)nicotinic acid wasused in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 464.4[M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 5.17 (s, 1H), 7.20-7.39 (m, 3H),7.39-7.61 (m, 5H), 7.60-7.72 (m, 1H), 8.05 (d, J=8.6 Hz, 1H), 8.34-8.53(m, 2H), 8.93 (d, J=2.3 Hz, 1H), 9.30 (s, 1H), 9.46 (s, 1H), 11.03 (s,1H).

Example 226

Example 226 was prepared using a procedure similar to that used toprepare Example 20 where 2-(pyridin-4-yl)benzoic acid was used in placeof 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 473.3 [M+H]⁺. ¹H NMR(300 MHz, DMSO-d₆) δ 4.94 (d, J=8.5 Hz, 1H), 7.21-7.37 (m, 5H),7.38-7.58 (m, 6H), 7.66 (tdd, J=6.8, 3.6, 1.7 Hz, 3H), 7.84 (dd, J=7.3,1.9 Hz, 1H), 8.46-8.56 (m, 2H), 8.98 (d, J=8.6 Hz, 1H), 10.93 (s, 1H).

Example 227

Example 227 was prepared using a procedure similar to that used toprepare Example 20 where piperidin-4-yl-L-proline was used in place of5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 472.3 [M+H]⁺. H NMR (300MHz, DMSO-d₆) δ 1.42 (m, 2H), 1.82 (m, 6H), 2.09 (m, 1H), 2.62-2.79 (m,2H), 2.85 (s, 1H), 3.00 (m, 4H), 4.06-4.16 (m, 1H), 5.07 (d, J=8.5 Hz,1H), 7.22-7.40 (m, 3H), 7.51 (q, J=7.9, 6.9 Hz, 5H), 7.61-7.74 (m, 1H),8.37-8.44 (s, 1H), 8.82 (d, J=8.7 Hz, 1H), 10.92 (s, 1H).

Example 228

A solution of Example 227 (188 mg, 0.4 mmol), HCHO (0.5 mL), NaBH(OAc)₃(212 mg, 1.0 mmol) in THF (20 mL) was stirred for 1 hour at 50° C.Extracted with EA (3×), dried Na₂SO₄, filtered and purified by Prep-HPLC(MeCN/H₂O) to give desired compound as a yellow solid (10 mg, 26%).ESI-MS m/z: 486.4 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 1.22-1.46 (m, 2H),1.63-1.96 (m, 8H), 2.10 (s, 3H), 2.22 (m, 1H), 2.68 (m, 3H), 2.85 (m,1H), 4.08 (m, 1H), 5.07 (m, 1H), 7.22-7.39 (m, 3H), 7.40-7.73 (m, 6H),8.78 (m, 1H), 10.94 (s, 1H).

Example 229

Example 229 was prepared using a procedure similar to that used toprepare Example 20 where 2-(2-methoxyethoxy)benzoic acid was used inplace of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 470.4 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 3.27 (s, 3H), 3.61-3.72 (m, 2H), 4.18 (dd,J=5.6, 3.8 Hz, 2H), 5.15 (d, J=8.5 Hz, 1H), 7.08 (td, J=7.5, 1.0 Hz,1H), 7.16-7.39 (m, 4H), 7.41-7.57 (m, 6H), 7.67 (ddd, J=8.4, 5.0, 1.8Hz, 2H), 9.00 (d, J=8.6 Hz, 1H), 10.98 (s, 1H).

Example 230

Example 230 Step a

A solution of3-amino-1-(4-methoxybenzyl)-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one,from Example 91 step b, (1.0 g, 2.70 mmol), benzaldehyde (314 mg, 2.96mmol), 4 A molecular sieves (10 g) and MgSO₄ (10 g) in 50 mL DCM wasstirred at room temperature overnight under N₂. Then the solid wasfiltered out and the filtrate was concentrated to afford crude product,which was used directly in the next step. ESI-MS m/z: 460.3 [M+H]⁺.

Example 230 Step b

A solution of the compound from step a (1.0 g, 2.18 mmol) in THF (20 mL)was added to NaHMDS (2.4 mL) in THF (5 mL) at −70° C. under N₂. Afterstirring for 5 min, MeI (340 mg, 2.40 mmol) was added. The mixture wasstirred at −70° C. for 2 hrs, then it was warmed to room temperature andstirred overnight. It was quenched by brine and solvent was removed. Theresidue was dissolved in 2N HCl (10 mL) and MeOH (5 mL). The mixture wasstirred for 30 min, basified by 2N NaOH and extracted with EtOAc. It waspurified silica gel column to afford product as tin solid (160 mg).ESI-MS m/z: 386.1 [M+H]⁺.

Example 230 Step c

A solution of the compound from step b (150 mg, 0.39 mmol) and Et₃N (79mg, 0.78 mmol) in DCM (5 mL) was added thiophosgene (49 mg, 0.43 mmol)at 0° C. After stirring for 2 hrs at 0° C., 4-fluorobenzohydrazide (200mg, 1.3 mmol) was added. It was stirred for another one hour beforeconcentrated. The residue was purified by reverse phase C18 columnchromatography (MeCN/H₂O) to afford product as yellow solid (70 mg).ESI-MS m/z: 582.4 [M+H]⁺.

Example 230 Step d

A mixture of the compound from step c (70 mg, 0.12 mmol) and EDCI (44mg, 0.24 mmol) in DMF (2 mL) was heated to 60° C. for 1 hour. Then itwas purified by reverse phase C18 column chromatography (MeCN/H₂O) toafford product as yellow solid (48 mg). ESI-MS m/z: 548.4 [M+H]⁺.

Example 230 Step g

A mixture of the compound from step d (48 mg, 0.087 mmol) and AlCl₃ (200mg, 1.5 mmol) in anisole (5 mL) was heated to 70° C. for 5 hrs under N₂.Solvent was removed. The residue was purified by prep-TLC to affordproduct as yellow solid (6 mg). ESI-MS m/z: 428.0 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 1.25 (s, 3H), 7.05-7.31 (m, 3H), 7.34-7.62 (m, 8H),7.75-7.90 (m, 2H), 8.23 (s, 1H), 11.02 (s, 1H).

Example 231

Example 231 was prepared using a procedure similar to that used toprepare Example 20 where 4-(1H-imidazol-1-yl)benzoic acid was used inplace of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 462.2 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 5.15 (s, 1H), 7.16 (s, 1H), 7.24-7.28 (m, 1H),7.34-7.36 (m, 2H), 7.45-7.48 (m, 2H), 7.51-7.55 (m, 3H), 7.60-7.65 (m,1H), 7.67-7.69 (m, 3H), 7.86-7.89 (m, 2H), 7.93-7.95 (m, 1H), 8.39 (s,1H), 11.03-11.04 (s, 1H).

Example 232

Example 232 was prepared using a procedure similar to that used toprepare Example 20 where 6-(1H-imidazol-1-yl)nicotinic acid was used inplace of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 463.0 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 1.23 (s, 1H), 5.19 (d, J=8.3 Hz, 1H), 7.14-7.74(m, 11H), 7.97-8.07 (m, 2H), 8.36 (dd, J=8.6, 2.3 Hz, 1H), 8.63 (s, 1H),8.89 (d, J=2.2 Hz, 1H), 9.28 (d, J=8.5 Hz, 1H), 11.02 (s, 1H).

Example 233

Example 233 was prepared using a procedure similar to that used toprepare Example 20 where 4-(4H-1,2,4-triazol-4-yl)benzoic acid was usedin place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 463.0 [M+H]⁺.H-NMR-PH-ETA-A1-433-0: ¹H NMR (300 MHz, DMSO-d₆) δ 5.18 (d, J=8.0 Hz,1H), 7.22-7.60 (m, 8H), 7.68 (ddd, J=8.4, 7.1, 1.7 Hz, 1H), 7.86-8.04(m, 4H), 9.23 (s, 3H), 11.01 (s, 1H).

Example 234

Example 234 was prepared using a procedure similar to that used toprepare Example 20 where 2-(2-(dimethylamino)ethoxy)benzoic acid wasused in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 483.5[M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 2.18 (s, 6H), 2.63 (t, J=5.9 Hz,2H), 4.13 (t, J=5.9 Hz, 2H), 5.14 (d, J=8.6 Hz, 1H), 7.07 (td, J=7.5,1.0 Hz, 1H), 7.16-7.59 (m, 10H), 7.61-7.73 (m, 2H), 8.96 (d, J=8.7 Hz,1H), 10.97 (s, 1H).

Example 235

Example 235 was prepared using a procedure similar to that used toprepare Example 20 where 2-((pyridin-2-ylmethyl)amino)benzoic acid wasused in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 496.2[M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 4.60 (d, J=5.4 Hz, 2H), 5.17 (d,J=8.5 Hz, 1H), 6.68-6.83 (m, 2H), 7.22-7.81 (m, 14H), 8.02 (t, J=5.5 Hz,1H), 8.46 (s, 1H), 8.51-8.60 (m, 1H), 9.15 (d, J=8.5 Hz, 1H), 11.01 (s,1H).

Example 236

Example 236 step a:

A solution of methyl 4-hydroxybenzoate (1.52 g, 10 mmol),2-methoxyethanol (1.52 g, 20 mmol), DIAD (5 mL) and PPh₃ (5 mL) in THF(50 mL) was stirred for overnight at rt. It was used directly to thenext step. ESI-MS m/z: 211.2 [M+H]⁺.

Example 236 Step b

NaOH (50 mL, 3.0 M) was added to the reaction mixture in step a, andthen it was stirred for 4 hours at rt. It was concentrated, andextracted with EA (×3) and washed with brine (×2). The water layers werecombined and adjusted pH to 1-2 with HCl, and then extracted with EA(×3) and washed with brine (×2). The organic layers were combinedconcentrated to give desired compound as a white solid (900 mg, 46%).ESI-MS m/z: 196.8 [M+H]⁺.

Example 236

Example 236 was prepared using a procedure similar to that used toprepare Example 20 where 4-(2-methoxyethoxy)benzoic acid was used inplace of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 470.1 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 3.31 (s, 3H), 3.58-3.73 (m, 2H), 4.08-4.24 (m,2H), 5.14 (d, 1H), 7.05-7.18 (d, 2H), 7.18-7.38 (m, 3H), 7.40-7.57 (m,5H), 7.56-7.87 (m, 3H), 9.03 (d, 1H), 10.99 (s, 1H).

Example 237

Example 237 was prepared using a procedure similar to that used toprepare Example 20 where 2-(4-methylpiperazin-1-yl)nicotinic acid wasused in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 495.2[M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 2.16 (s, 6H), 2.36 (t, J=4.7 Hz,4H), 3.15 (dd, J=5.6, 3.7 Hz, 4H), 5.15 (d, J=8.5 Hz, 1H), 6.99 (dd,J=7.6, 4.8 Hz, 1H), 7.22-7.60 (m, 8H), 7.67 (ddd, J=8.5, 7.1, 1.7 Hz,1H), 7.91 (dd, J=7.6, 1.9 Hz, 1H), 8.32 (dd, J=4.8, 1.9 Hz, 1H), 9.12(d, J=8.7 Hz, 1H), 10.98 (s, 1H).

Example 238

Example 238 was prepared using a procedure similar to that used toprepare Example 20 where (R)-2-(methylamino)-2-phenylacetic acid wasused in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 439.3[M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 2.24 (s, 3H), 4.84 (s, 1H), 5.03 (d,J=8.6 Hz, 1H), 7.19-7.58 (m, 13H), 7.65 (ddd, J=8.4, 6.9, 1.9 Hz, 1H),8.29 (s, 1H), 8.82 (dd, J=8.7, 2.4 Hz, 1H).

Example 239

Example 239 was prepared using a procedure similar to that used toprepare Example 20 where 2-((tetrahydro-2H-pyran-4-yl)oxy)benzoic acidwas used in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 496.2[M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 1.62 (ddt, J=11.6, 7.9, 4.7 Hz, 2H),1.88 (dd, J=12.4, 6.4 Hz, 2H), 3.38-3.51 (m, 2H), 3.81 (dt, J=10.2, 4.6Hz, 2H), 4.71 (tt, J=7.4, 3.7 Hz, 1H), 5.14 (d, J=8.6 Hz, 1H), 7.07 (t,J=7.4 Hz, 1H), 7.22-7.59 (m, 10H), 7.60-7.74 (m, 2H), 9.05 (d, J=8.6 Hz,1H), 10.98 (s, 1H).

Example 240

Example 240 was prepared using a procedure similar to that used toprepare Example 20 where 2-(1,1-dioxidothiomorpholino)benzoic acid wasused in place of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 529.3[M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 3.31 (s, 4H), 3.38 (d, J=4.9 Hz,4H), 5.17 (d, J=8.7 Hz, 1H), 7.19-7.39 (m, 5H), 7.42-7.58 (m, 6H),7.64-7.81 (m, 2H), 9.27 (d, J=8.7 Hz, 1H), 11.00 (s, 1H).

Example 241

Example 241 was prepared using a procedure similar to that used toprepare Example 20 where 2-(piperidin-1-yl)nicotinic acid was used inplace of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 480.2 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 1.54 (d, J=7.4 Hz, 6H), 3.10 (d, J=5.5 Hz, 4H),5.15 (d, J=8.7 Hz, 1H), 6.94 (dd, J=7.6, 4.8 Hz, 1H), 7.21-7.39 (m, 3H),7.40-7.59 (m, 5H), 7.67 (ddd, J=8.3, 7.0, 1.8 Hz, 1H), 7.88 (dd, J=7.6,1.9 Hz, 1H), 8.29 (dd, J=4.8, 1.9 Hz, 1H), 9.11 (d, J=8.7 Hz, 1H), 10.98(s, 1H).

Example 242

Example 242 was prepared using a procedure similar to that used toprepare Example 152 where ethyl 2-morpholinonicotinate, which wasprepared similarly to ethyl 3-morpholinopicolinate in Example 132 stepb, was used in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate.ESI-MS m/z: 482.1980 [M+H]⁺.

Example 243

Example 243 was prepared using a procedure similar to that used toprepare Example 161 where cis-2,6-dimethylmorpholine and ethyl2-chloro-4-fluorobenzoate were used in place of morpholine and methyl5-chloropyrazine-2-carboxylate, respectively. ESI-MS m/z: 543.3 [M+H]⁺.

Example 244

Example 244 was prepared using a procedure similar to that used toprepare Example 161 where (1R,5S)-3-oxa-8-azabicyclo[3.2.1]octane andethyl 2-chloro-4-fluorobenzoate were used in place of morpholine andmethyl 5-chloropyrazine-2-carboxylate, respectively. ESI-MS m/z: 541.3[M+H]⁺.

Example 245

Example 245 Step a

A solution of methyl 2-fluoronicotinate (1 g, 6.5 mmol),(R)-3-methylmorpholine (722 mg, 7.2 mmol) and K₂CO₃ (1.79 g, 13.0 mmol)in DMSO (5 mL) was stirred for 1 hour at 100° C. It was diluted withwater, extracted with EA (×3), washed with brine (×2), the organiclayers was combined, dried, concentrated to give 1.2 g (crude) ofdesired compound as a colourless oil, which was used directly in thenext step. ESI-MS m/z: 237.1 [M+H]⁺.

Example 245 Step b

A solution of the compound from step a (1.2 g, 5.0 mol) and NH₂NH₂.H₂O(5 mL) in EtOH (10 mL) was refluxed for 2 hours. It was concentrated andpurified by Prep-HPLC (MeCN/H₂O) to give the desired compound as a whitesolid (1 g, 83%). ESI-MS m/z: 237.1 [M+H]⁺.

Example 245 Step c

Example 245 was prepared using a procedure similar to that used toprepare Example 21 where (R)-2-(3-methylmorpholino)nicotinohydrazide wasused in place of tetrahydro-2H-pyran-4-carbohydrazide. ESI-MS m/z: 496.1[M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 1.00 (m, 3H), 3.03-3.04 (m, 1H),3.24-3.25 (m, 1H), 3.38-3.79 (m, 5H), 5.15 (m, 1H), 7.03 (m, 1H), 7.32(m, 3H), 7.41-7.60 (m, 5H), 7.67 (m, 1H), 7.95 (m, 1H), 8.33-8.41 (m,1H), 9.15 (m, 1H), 10.98 (s, 1H).

Example 246

Example 246 was prepared using a procedure similar to that used toprepare Example 245 where 3,3-difluoropiperidine was used in place of(R)-3-methylmorpholine. ESI-MS m/z: 516.5 [M+H]⁺. H NMR (300 MHz,DMSO-d₆) δ 1.83 (d, J=7.3 Hz, 2H), 1.93-2.14 (m, 2H), 3.18 (d, J=6.1 Hz,2H), 3.43-3.58 (m, 2H), 5.16 (d, J=7.7 Hz, 1H), 7.08 (m, 1H), 7.22-7.61(m, 8H), 7.62-7.74 (m, 1H), 7.98 (m, 1H), 8.36 (m, 1H), 9.13 (d, J=8.0Hz, 1H), 11.00 (s, 1H).

Example 247

Example 247 was prepared using a procedure similar to that used toprepare Example 245 where (S)-3-methoxypyrrolidine was used in place of(R)-3-methylmorpholine. ESI-MS m/z: 496.5 [M+H]⁺. H NMR (300 MHz,DMSO-d₆) δ 1.84-2.01 (m, 2H), 3.10-3.50 (m, 7H), 3.96 (m, 1H), 5.14 (m,1H), 6.76 (m, 1H), 7.21-7.39 (m, 3H), 7.39-7.60 (m, 5H), 7.60-7.77 (m,2H), 8.26 (m, 1H), 9.01 (m, 1H), 10.95 (s, 1H).

Example 248

Example 248 was prepared using a procedure similar to that used toprepare Example 245 where (1 S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane wasused in place of (R)-3-methylmorpholine. ESI-MS m/z: 494.5 [M+H]⁺. H NMR(300 MHz, DMSO-d₆) δ 1.78 (s, 2H), 2.68 (m, 1H), 3.27-3.40 (m, 1H),3.70-3.83 (m, 2H), 4.53 (s, 1H), 4.70-4.80 (m, 1H), 5.13 (m, 1H), 6.84(m, 1H), 7.21-7.39 (m, 3H), 7.49 (m, 5H), 7.66 (m, 1H), 7.78 (m, 1H),8.27 (m, 1H), 9.03 (d, J=8.5 Hz, 1H), 10.96 (s, 1H).

Example 249

Example 249 was prepared using a procedure similar to that used toprepare Example 245 where 1,4-oxazepane was used in place of(R)-3-methylmorpholine. ESI-MS m/z: 496.5 [M+H]⁺. ¹H NMR (300 MHz,DMSO-d₆) δ 1.83 (m, 2H), 3.45 (m, 4H), 3.53-3.64 (m, 2H), 3.69 (m, 2H),5.13 (d, J=8.6 Hz, 1H), 6.83 (m, 1H), 7.21-7.39 (m, 3H), 7.40-7.59 (m,5H), 7.66 (m, 1H), 7.77 (m, 1H), 8.27 (m, 1H), 9.02 (d, J=8.6 Hz, 1H),10.96 (s, 1H).

Example 250

Example 250 was prepared using a procedure similar to that used toprepare Example 160 where 3-oxa-8-azabicyclo[3.2.1]octane and ethyl3-chloro-5-(trifluoromethyl)picolinate were used in place of morpholineand methyl 5-bromo-3-fluoropicolinate, respectively. ESI MS m/z=576.2[M+H]⁺.

Example 251

Example 251 was prepared using a procedure similar to that used toprepare Example 160 where 8-oxa-3-azabicyclo[3.2.1]octane and ethyl3-chloro-5-(trifluoromethyl)picolinate were used in place of morpholineand methyl 5-bromo-3-fluoropicolinate, respectively. ESI MS m/z=576.2[M+H]⁺.

Example 252

Example 252 was prepared using a procedure similar to that used toprepare Example 160 where methyl 2-chloro-6-methylnicotinate was used inplace of methyl 5-bromo-3-fluoropicolinate. ESI MS m/z=496.2 [M+H]⁺.

Example 253

Example was prepared using a procedure similar to that used to prepareExample 160 where ethyl 3-chloro-5-(trifluoromethyl)picolinate was usedin place of methyl 5-bromo-3-fluoropicolinate. ESI-MS m z: 550.2 [M+H]⁺.

Example 254

Example 254 was prepared using a procedure similar to that used toprepare Example 245 where 4-methoxypiperidine was used in place of(R)-3-methylmorpholine. ESI-MS m/z: 510.5 [M+H]⁺. ¹H NMR (300 MHz,DMSO-d₆) δ 1.53 (m, 2H), 1.85 (s, 1H), 2.85-2.99 (m, 2H), 3.23 (s, 6H),5.15 (d, J=8.5 Hz, 1H), 6.96 (m, 1H), 7.21-7.59 (m, 8H), 7.67 (m, 1H),7.90 (m, 1H), 8.30 (m, 1H), 9.12 (d, J=8.6 Hz, 1H), 10.97 (s, 1H).

Example 255

Example 255 was prepared using a procedure similar to that used toprepare Example 245 where piperidin-4-ol was used in place of(R)-3-methylmorpholine. ESI-MS m/z: 496.4 [M+H]⁺. ¹H NMR (300 MHz,DMSO-d₆) δ 1.47 (m, 2H), 1.68-1.81 (m, 2H), 2.83-2.97 (m, 2H), 3.57-3.70(m, 1H), 4.66 (s, 1H), 5.15 (d, J=8.6 Hz, 1H), 6.94 (m, 1H), 7.21-7.40(m, 3H), 7.39-7.59 (m, 5H), 7.67 (m, 1H), 7.88 (m, 1H), 8.30 (m, 1H),9.10 (d, J=8.6 Hz, 1H), 10.97 (s, 1H).

Example 256

Example 256 was prepared using a procedure similar to that used toprepare Example 245 where 4-fluoropiperidine was used in place of(R)-3-methylmorpholine. ESI-MS m/z: 498.4 [M+H]⁺. ¹H NMR (300 MHz,DMSO-d₆) δ 1.72-1.88 (m, 4H), 1.94 (d, J=19.8 Hz, 4H), 3.11 (m, 4H),4.75 (m, 1H), 5.15 (d, J=8.6 Hz, 2H), 7.01 (m, 2H), 7.32 (m, 6H),7.39-7.62 (m, 10H), 7.67 (m, 2H), 7.94 (m, 2H), 8.33 (m, 2H), 9.15 (d,J=8.6 Hz, 2H), 10.97 (s, 2H).

Example 257

Example 257 was prepared using a procedure similar to that used toprepare Example 245 where (R)-3-methoxypyrrolidine was used in place of(R)-3-methylmorpholine. ESI-MS m/z: 496.4 [M+H]⁺. ¹H NMR (300 MHz,DMSO-d₆) δ 1.94 (m, 2H), 3.09-3.50 (m, 7H), 3.96 (m, 1H), 5.14 (m, 1H),6.76 (m, 1H), 7.21-7.39 (m, 3H), 7.39-7.60 (m, 5H), 7.60-7.77 (m, 2H),8.26 (m, 1H), 9.01 (m, 1H), 10.97 (s, 1H).

Example 258

Example 258 was prepared using a procedure similar to that used toprepare Example 245 where 3-methoxyazetidine was used in place of(R)-3-methylmorpholine. ESI-MS m/z: 482.4 [M+H]⁺. ¹H NMR (300 MHz,DMSO-d₆) δ 3.19 (s, 3H), 3.73 (m, 2H), 4.02-4.26 (m, 3H), 5.15 (d, J=8.5Hz, 1H), 6.84 (m, 1H), 7.21-7.40 (m, 3H), 7.39-7.60 (m, 5H), 7.67 (m,1H), 7.79 (dd, J=7.6, 1.9 Hz, 1H), 8.28 (m, 1H), 9.09 (d, J=8.5 Hz, 1H),10.97 (s, 1H).

Example 259

Example 259 was prepared using a procedure similar to that used toprepare Example 245 where 3,3-difluoroazetidine was used in place of(R)-3-methylmorpholine. ESI-MS m/z: 488.4 [M+H]⁺. H NMR (300 MHz,DMSO-d₆) δ 4.41 (m, 4H), 5.18 (d, J=8.3 Hz, 1H), 7.05 (m, 1H), 7.21-7.78(m, 9H), 7.97 (m, 1H), 8.37 (m, 1H), 9.20 (d, J=8.5 Hz, 1H), 11.01 (s,1H).

Example 260

Example 260 was prepared using a procedure similar to that used toprepare Example 245 where piperidine-4-carbonitrile was used in place of(R)-3-methylmorpholine. ESI-MS m/z: 505.3 [M+H]⁺. H NMR (300 MHz,DMSO-d₆) δ 1.77-2.03 (m, 4H), 3.03 (m, 3H), 3.31 (d, J=6.8 Hz, 2H), 5.16(s, 1H), 7.04 (m, 1H), 7.22-7.40 (m, 3H), 7.40-7.60 (m, 5H), 7.67 (m,1H), 7.97 (m, 1H), 8.34 (m, 1H), 9.21 (s, 1H), 9.80 (s, 1H).

Example 261

Example 261 was prepared using a procedure similar to that used toprepare Example 245 where (S)-3-methylmorpholine was used in place of(R)-3-methylmorpholine. ESI-MS m/z: 496.5 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 1.02 (m, 3H), 2.99-3.09 (m, 1H), 3.29 (m, 1H), 3.47 (m, 1H),3.52-3.82 (m, 4H), 5.18 (m, 1H), 7.05 (m, 1H), 7.29 (m, 1H), 7.36 (m,2H), 7.43-7.59 (m, 5H), 7.64-7.71 (m, 1H), 7.97 (m, 1H), 8.38 (m, 1H),9.13-9.34 (m, 1H), 11.01 (s, 1H).

Example 262

Example 262 was prepared using a procedure similar to that used toprepare Example 245 where (R)-2-methylmorpholine was used in place of(R)-3-methylmorpholine. ESI-MS m/z: 496.4 [M+H]⁺. ¹H NMR (300 MHz,DMSO-d₆) δ 1.06 (d, J=6.1 Hz, 3H), 2.53-2.62 (m, 1H), 2.84 (m, 1H), 3.41(m, 2H), 3.55-3.70 (m, 2H), 3.76 (s, 1H), 5.12-5.18 (m, 1H), 7.02 (m,1H), 7.22-7.41 (m, 3H), 7.42-7.57 (m, 5H), 7.67 (m, 1H), 7.95 (m, 1H),8.25-8.36 (m, 1H), 9.09-9.20 (m, 1H).

Example 263

Example 263 was prepared using a procedure similar to that used toprepare Example 245 where (S)-2-methylmorpholine was used in place of(R)-3-methylmorpholine. ESI-MS m/z: 496.2 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 1.08 (d, J=6.2 Hz, 3H), 2.57 (d, J=10.1 Hz, 1H), 2.86 (m,1H), 3.39 (m, 2H), 3.58-3.93 (m, 3H), 5.18 (d, J=8.2 Hz, 1H), 7.03 (m,1H), 7.29 (m, 1H), 7.36 (m, 2H), 7.50 (m, 5H), 7.68 (m, 1H), 7.97 (d,J=7.6 Hz, 1H), 8.27-8.51 (m, 1H), 9.18 (m, 1H), 10.83-11.23 (m, 1H).

Example 264

Example 264 was prepared using a procedure similar to that used toprepare Example 245 where (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane wasused in place of (R)-3-methylmorpholine. ESI-MS m/z: 494.5 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 1.79 (s, 2H), 2.71 (m, 1H), 3.37 (m, 1H),3.70-3.90 (m, 2H), 4.54 (s, 1H), 4.76 (m, 1H), 5.15 (m, 1H), 6.85 (m,1H), 7.24-7.41 (m, 3H), 7.44-7.60 (m, 5H), 7.67 (m, 1H), 7.80 (m, 1H),8.29 (m, 1H), 9.03 (d, J=8.5 Hz, 1H), 10.98 (s, 1H).

Example 265

Example 265 was prepared using a procedure similar to that used toprepare Example 245 where 3-oxa-8-azabicyclo[3.2.1]octane was used inplace of (R)-3-methylmorpholine. ESI-MS m/z: 508.2 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 1.72-1.79 (m, 2H), 1.81-1.84 (m, 2H), 3.48-3.50 (m, 2H),3.73-3.78 (m, 2H), 3.96-4.03 (m, 2H), 5.14-5.16 (d, J=8.0, 1H),6.94-6.98 (m, 1H), 7.26-7.29 (m, 1H), 7.33-7.35 (m, 2H), 7.44-7.53 (m,5H), 7.54-7.55 (m, 1H), 7.65-7.69 (m, 1H), 7.89-7.92 (m, 1H),8.29-8.30-9.42 (m, 1H), 9.14-9.16 (d, J=8.0, 1H), 10.97 (s, 1H).

Example 266

Example 266 was prepared using a procedure similar to that used toprepare Example 245 where 8-oxa-3-azabicyclo[3.2.1]octane was used inplace of (R)-3-methylmorpholine. ESI-MS m/z: 508.1 [M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 1.63-1.80 (m, 2H), 1.89 (dd, J=7.4, 4.6 Hz, 2H), 3.01(dt, J=12.5, 2.2 Hz, 2H), 3.28 (dd, J=11.4, 3.3 Hz, 2H), 4.28 (dd,J=4.4, 2.3 Hz, 2H), 5.15 (d, J=8.6 Hz, 1H), 6.97 (dd, J=7.6, 4.7 Hz,1H), 7.32 (ddd, J=18.4, 7.4, 1.3 Hz, 3H), 7.41-7.60 (m, 5H), 7.67 (ddd,J=8.4, 7.0, 1.7 Hz, 1H), 7.85 (dd, J=7.6, 1.9 Hz, 1H), 8.32 (dd, J=4.8,1.9 Hz, 1H), 9.12 (d, J=8.6 Hz, 1H), 10.97 (s, 1H).

Example 267

Example 267 was prepared using a procedure similar to that used toprepare Example 245 where (3aR,6aS)-hexahydro-1H-furo[3,4-c]pyrrole wasused in place of (R)-3-methylmorpholine. ESI-MS m/z: 508.5 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 2.90 (dq, J=7.5, 4.1 Hz, 2H), 3.16 (ddd,J=10.8, 5.9, 3.1 Hz, 2H), 3.37-3.60 (m, 4H), 3.80 (dd, J=8.7, 6.2 Hz,2H), 5.17 (d, J=8.5 Hz, 1H), 6.84 (dd, J=7.5, 4.8 Hz, 1H), 7.33 (dd,J=18.6, 7.8 Hz, 3H), 7.42-7.63 (m, 5H), 7.63-7.84 (m, 2H), 8.30 (dd,J=4.7, 1.8 Hz, 1H), 9.07 (d, J=8.6 Hz, 1H), 10.98 (s, 1H).

Example 268

Example 268 was prepared using a procedure similar to that used toprepare Example 160 where 4-methoxypiperidine and ethyl3-chloro-5-(trifluoromethyl)picolinate were used in place of morpholineand methyl 5-bromo-3-fluoropicolinate, respectively. ESI-MS m/z: 578.2[M+H]⁺.

Example 269

Example 269 was prepared using a procedure similar to that used toprepare Example 160 where 4-fluoropiperidine and ethyl3-chloro-5-(trifluoromethyl)picolinate were used in place of morpholineand methyl 5-bromo-3-fluoropicolinate, respectively. ESI-MS m/z: 566.2[M+H]⁺.

Example 270

Example 270 was prepared using a procedure similar to that used toprepare Example 245 where5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine was used in place of(R)-3-methylmorpholine. ESI-MS m/z: 519.2 [M+H]⁺. ¹H NMR (300 MHz,DMSO-d₆) δ 3.68 (q, J=4.6 Hz, 2H), 4.30 (t, J=5.4 Hz, 2H), 4.59 (d,J=2.6 Hz, 2H), 5.13 (s, 1H), 7.12-7.74 (m, 10H), 7.96 (s, 1H), 8.08 (dd,J=7.7, 1.9 Hz, 1H), 8.41 (dd, J=4.8, 1.9 Hz, 1H), 9.17 (s, 1H).

Example 271

Example 271 was prepared using a procedure similar to that used toprepare Example 160 where 3-methoxyazetidine and ethyl3-chloro-5-(trifluoromethyl)picolinate were used in place of morpholineand methyl 5-bromo-3-fluoropicolinate, respectively. ESI MS m/z=550.1830[M+H]⁺.

Example 272

Example 272 step a:

In an oven-dried vial, methyl 2-methyl-5-bromothiazole-4-carboxylate(0.5 g, 2.12 mmol) was dissolved in morpholine (4 ml, 46.4 mmol) andsealed. The reaction was heated to 60° C. and stirred overnight. Thereaction mixture was concentrated, removing excess morpholine. The crudeproduct was added to a silica gel column and was eluted with ethylacetate/hexane 0% to 100% to give methyl2-methyl-5-morpholinothiazole-4-carboxylate (0.126 g, 25% yield) as awhite solid. ESI MS m/z=243.1 [M+H]⁺.

Example 272 Step b

Example 272 was prepared using a procedure similar to that used toprepare Example 152 where methyl2-methyl-5-morpholinothiazole-4-carboxylate was used in place of ethyl2-morpholino-4-(trifluoromethyl)benzoate. ESI MS m/z=502.2 [M+H]⁺.

Example 273

Example 273 was prepared using a procedure similar to that used toprepare Example 20 where 4-(1H-1,2,4-triazol-1-yl)benzoic acid was usedin place of 5-chlorofuran-2-carboxylic acid. ESI MS m/z=463.2 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 5.18-5.20 (d, J=8.0, 1H), 7.27-7.29 (m, 1H),7.31-7.35 (m, 2H), 7.37-7.45 (m, 2H), 7.47-7.51 (m, 3H), 7.53-7.56 (m,1H), 7.66-7.70 (m, 2H), 7.71-7.99 (m, 2H), 8.00-8.09 (m, 1H), 9.22-9.24(m, 1H), 9.42 (s, 1H), 11.00 (s, 1H).

Example 274

Example 274 was prepared using a procedure similar to that used toprepare Example 245 where azetidine-3-carbonitrile was used in place of(R)-3-methylmorpholine. ESI-MS m/z: 477.2 [M+H]⁺. ¹H NMR (300 MHz,Methanol-d₄) δ 3.69 (tt, J=8.9, 6.0 Hz, 1H), 4.22 (ddd, J=8.4, 6.2, 1.5Hz, 2H), 4.35 (td, J=8.8, 2.4 Hz, 2H), 5.30 (s, 1H), 6.95 (dd, J=7.7,4.9 Hz, 1H), 7.23-7.72 (m, 10H), 7.98 (dd, J=7.7, 1.8 Hz, 1H), 8.32 (dd,J=4.9, 1.8 Hz, 1H), 8.52 (s, 2H).

Example 275

Example 275 was prepared using a procedure similar to that used toprepare Example 160 where 3-oxa-8-azabicyclo[3.2.1]octane and ethyl2-chloro-6-(trifluoromethyl)nicotinate were used in place of morpholineand methyl 5-bromo-3-fluoropicolinate, respectively. ESI-MS m/z: 576.3[M+H]⁺.

Example 276

Example 276 was prepared using a procedure similar to that used toprepare Example 160 where 3-oxa-8-azabicyclo[3.2.1]octane and ethyl2-chloro-6-(trifluoromethyl)nicotinate were used in place of morpholineand methyl 5-bromo-3-fluoropicolinate, respectively. ESI-MS m/z: 576.3[M+H]⁺.

Example 277

Example 277 was prepared using a procedure similar to that used toprepare Example 160 where (R)-2-methylmorpholine and ethyl3-chloro-5-(trifluoromethyl)picolinate were used in place of morpholineand methyl 5-bromo-3-fluoropicolinate, respectively. ESI-MS m/z: 564.3[M+H]⁺.

Example 278

Example 278 was prepared using a procedure similar to that used toprepare Example 160 where (S)-2-methylmorpholine and ethyl3-chloro-5-(trifluoromethyl)picolinate were used in place of morpholineand methyl 5-bromo-3-fluoropicolinate, respectively. ESI-MS m/z: 564.3[M+H]⁺.

Example 279

Example 279 was prepared using a procedure similar to that used toprepare Example 160 where 3-oxa-8-azabicyclo[3.2.1]octane and methyl2-chloro-6-methylnicotinate were used in place of morpholine andmethy5-bromo-3-fluoropicolinate, respectively. ESI-MS m/z: 522.3 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 1.62-1.81 (m, 2H), 1.90 (dd, J=7.2, 4.8 Hz,2H), 2.41 (s, 3H), 3.00 (dt, J=12.6, 2.0 Hz, 2H), 3.28 (s, 2H),4.18-4.38 (m, 2H), 5.15 (d, J=8.5 Hz, 1H), 6.85 (d, J=7.7 Hz, 1H), 7.29(td, J=7.4, 1.2 Hz, 1H), 7.36 (dd, J=7.7, 1.4 Hz, 1H), 7.44-7.58 (m,5H), 7.68 (ddd, J=8.6, 7.2, 1.7 Hz, 1H), 7.74 (d, J=7.7 Hz, 1H), 9.10(d, J=8.7 Hz, 1H), 10.99 (s, 1H).

Example 280

Example 280 was prepared using a procedure similar to that used toprepare Example 160 where 8-oxa-3-azabicyclo[3.2.1]octane and methyl2-chloro-6-methylnicotinate were used in place of morpholine andmethy5-bromo-3-fluoropicolinate, respectively. ESI-MS m/z: 522.3 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 1.77 (m, 4H), 2.39 (s, 3H), 3.44-3.53 (d,2H), 3.70-3.81 (m, 2H), 3.94-4.08 (d, 2H), 5.15 (d, 1H), 6.83 (d, 1H),7.32 (d, 3H), 7.41-7.60 (m, 5H), 7.67 (m, 1H), 7.79 (d, 1H), 9.10 (d,1H), 10.98 (s, 1H).

Example 281

Example 281 was prepared using a procedure similar to that used toprepare Example 151 where2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-cyanobenzoic acid, which wasprepared similarly to 4-cyano-2-morpholinobenzoic acid in Example 131,was used in place of 6-fluoro-2-morpholinonicotinic acid. ESI-MS m/z:532.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 1.60-1.82 (m, 2H), 1.95-2.11(m, 2H), 2.80-2.99 (m, 4H), 4.19-4.35 (m, 2H), 5.18 (d, J=8.6 Hz, 1H),7.26-7.74 (m, 12H), 9.27 (dd, J=8.5, 1.6 Hz, 1H), 11.00 (s, 1H).

Example 282

Example 282 Step a

A solution of the ethyl 3-chloro-5-(trifluoromethyl)picolinate (1 g, 4.0mmol), pyridin-4-ylboronic acid (583 mg, 4.7 mmol), Pd(dppf)Cl₂. DCM(1.8 g, 2.2 mol) and Na₂CO₃ (848 mg, 8.0 mol) in DMF (5 mL) was stirredfor 1 hour at 130° C. It was purified by reverse phase C18 columnchromatography (MeCN/H₂O) to give ethyl5-(trifluoromethyl)-[3,4′-bipyridine]-2-carboxylate as a white solid(513 mg, 43%). ESI-MS m/z: 297.0 [M+H]⁺.

Example 282 Step b

Example 282 was prepared using a procedure similar to that used toprepare Example 152 where ethyl5-(trifluoromethyl)-[3,4′-bipyridine]-2-carboxylate was used in place ofethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI-MS m/z: 542.2[M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 5.07 (d, J=7.8 Hz, 1H), 7.21-7.36(m, 3H), 7.37-7.58 (m, 6H), 7.65 (m, 1H), 8.31-8.38 (m, 1H), 8.55-8.63(m, 2H), 9.21 (m, 1H), 9.42 (d, J=8.4 Hz, 1H), 10.93 (s, 1H).

Example 283

Example 283 was prepared using a procedure similar to that used toprepare Example 20 where 2-(1H-pyrazol-1-yl)benzoic acid was used inplace of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 462.4 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 4.89 (d, J=8.6 Hz, 1H), 6.13-6.19 (m, 1H),7.24-7.78 (m, 13H), 7.81-7.91 (m, 1H), 7.95-8.05 (m, 1H), 8.91 (d, J=8.6Hz, 1H), 10.94 (s, 1H).

Example 284

Example 284 was prepared using a procedure similar to that used toprepare Example 159 where ethyl2-(cis-2,6-dimethylmorpholino)-4-fluorobenzoate was used in place ofethyl 4-fluoro-2-morpholinobenzoate. ESI-MS m/z: 527.2 [M+H]⁺.

Example 285

Example 285 was prepared using a procedure similar to that used toprepare Example 151 where (R)-4-cyano-2-(3-methylmorpholino)benzoicacid, which was prepared similarly to 4-cyano-2-morpholinobenzoic acidin Example 131, was used in place of 6-fluoro-2-morpholinonicotinicacid. ESI-MS m/z: 520.6 [M+H]⁺.

Example 286

Example 286 was prepared using a procedure similar to that used toprepare Example 160 where (R)-3-methylmorpholine and methyl2-chloro-6-methylnicotinate were used in place of morpholine andmethy5-bromo-3-fluoropicolinate, respectively. ESI-MS m/z: 510.2 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 0.99-1.01 (m, 3H), 2.50-2.51 (m, 3H),3.03-3.07 (m, 1H), 3.22-3.26 (m, 1H), 3.33-3.46 (m, 1H), 3.50-3.53 (m,1H), 3.57-3.69 (m, 1H), 3.73-3.78 (m, 2H), 5.14-5.16 (d, J=8.0, 1H),6.89-6.91 (d, J=8.0, 1H), 7.26-7.36 (m, 3H), 7.44-7.55 (m, 5H),7.65-7.70 (m, 1H), 7.82-7.84 (m, 1H), 9.08-9.11 (d, J=12.0, 1H), 10.98(s, 1H).

Example 287

Example 287 was prepared using a procedure similar to that used toprepare Example 20 where quinuclidine-4-carboxylic acid was used inplace of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 390.1 [M+H]⁺. HNMR (300 MHz, DMSO-d₆) δ 1.69 (m, 6H), 2.76-2.88 (m, 6H), 5.03 (d, J=8.7Hz, 1H), 7.19-7.37 (m, 3H), 7.38-7.59 (m, 5H), 7.65 (m, 1H), 8.72 (d,J=8.7 Hz, 1H), 10.88 (s, 1H).

Example 288

Example 288 was prepared using a procedure similar to that used toprepare Example 159 where ethyl2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-fluorobenzoate was used inplace of ethyl 4-fluoro-2-morpholinobenzoate. ESI-MS m/z: 525.2 [M+H]⁺.

Example 289

Example 289 was prepared using a procedure similar to that used toprepare Example 151 where2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-cyanobenzoic acid, which wasprepared similarly to 4-cyano-2-morpholinobenzoic acid in Example 131,was used in place of 6-fluoro-2-morpholinonicotinic acid. ESI-MS m/z:532.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 1.82-1.85 (m, 4H), 3.45-3.48(m, 2H), 3.69-3.80 (m, 4H), 5.15-5.17 (m, 1H), 7.26-7.33 (m, 2H),4.53-4.54 (m, 1H), 7.35-7.44 (m, 3H), 7.46-7.55 (m, 6H), 7.65-7.74 (m,2H), 9.24-9.26 (d, J=8.0, 1H), 10.97 (s, 1H).

Example 290

Example 290 was prepared using a procedure similar to that used toprepare Example 162 where 8-oxa-3-azabicyclo[3.2.1]octane was used inplace of morpholine. ESI-MS m/z: 551.6 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆)δ 1.69 (m, 4H), 3.22 (d, J=12.9 Hz, 2H), 3.67 (m, 2H), 4.35 (s, 2H),5.15 (d, J=6.9 Hz, 1H), 7.26 (m, 1H), 7.34 (d, J=8.2 Hz, 2H), 7.48 (m,5H), 7.65 (m, 1H), 8.66 (s, 1H), 9.24 (d, J=7.9 Hz, 1H), 10.98 (s, 1H).

Example 291

Example 291 was prepared using a procedure similar to that used toprepare Example 20 where 3-cyano-1H-indole-6-carboxylic acid was used inplace of 5-chlorofuran-2-carboxylic acid. ESI-MS m/z: 460.1 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 5.19 (d, J=8.6 Hz, 1H), 7.24-7.89 (m, 11H),7.96-8.03 (m, 1H), 8.44 (s, 1H), 9.16 (d, J=8.6 Hz, 1H), 11.02 (s, 1H),12.52 (s, 1H).

Example 292

Example 292 was prepared using a procedure similar to that used toprepare Example 272. ESI-MS in m/z: 489.1 [M+H]⁺.

Example 293

Example 293 was prepared using a procedure similar to that used toprepare Example 282. ESI-MS m/z: 505.1 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆)δ 0.92 (m, 2H), 1.10 (m, 2H), 2.90-3.00 (m, 1H), 5.20-5.23 (d, J=7.8 Hz,1H), 7.25-7.37 (m, 3H), 7.37-7.56 (m, 5H), 7.65 (m, 1H), 7.82 (s, 1H),8.89 (s, 1H), 9.41 (d, J=8.4 Hz, 1H), 10.98 (s, 1H).

Example 294

Example 294 was prepared using a procedure similar to that used toprepare Example 160 where (R)-3-methylmorpholine and ethyl3-chloro-5-(trifluoromethyl)picolinate were used in place of morpholineand methyl 5-bromo-3-fluoropicolinate, respectively. ESI-MS m/z: 564.4[M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 0.80 (d, J=6.3 Hz, 3H), 2.71-2.83(m, 2H), 3.35 (s, 2H), 3.50 (m, 1H), 3.58-3.68 (m, 1H), 3.78 (m, 2H),5.20 (d, J=8.3 Hz, 1H), 7.22-7.38 (m, 3H), 7.40-7.58 (m, 5H), 7.61-7.75(m, 1H), 8.04 (d, J=1.9 Hz, 1H), 8.45 (s, 0.29H), 8.72-8.78 (m, 1H),9.37 (d, J=8.5 Hz, 1H), 10.97 (s, 1H).

Example 295

Example 295 was prepared using a procedure similar to that used toprepare Example 160 where methyl 2-chloro-6-methoxynicotinate was usedin place of methy5-bromo-3-fluoropicolinate. ESI-MS m/z: 512.2 [M+H]⁺.¹H NMR (300 MHz, DMSO-d₆) δ 3.11-3.27 (m, 4H), 3.62 (s, 4H), 3.87 (s,3H), 5.13 (d, J=8.6 Hz, 1H), 6.40 (d, J=8.4 Hz, 1H), 7.18-7.40 (m, 3H),7.40-7.58 (m, 5H), 7.61-7.74 (m, 1H), 7.83 (d, J=8.3 Hz, 1H), 9.00 (d,J=8.7 Hz, 1H), 10.88 (s, 1H).

Example 296

Example 296 was prepared using a procedure similar to that used toprepare Example 160 where 1-methylpiperazin-2-one and ethyl3-chloro-5-(trifluoromethyl)picolinate were used in place of morpholineand methyl 5-bromo-3-fluoropicolinate, respectively. ESI-MS m/z: 577.3[M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 2.86 (s, 3H), 3.34 (d, J=4.6 Hz,2H), 3.44 (m, 2H), 3.78 (s, 2H), 5.19 (d, J=8.2 Hz, 1H), 7.22-7.39 (m,3H), 7.40-7.57 (m, 5H), 7.61-7.71 (m, 1H), 7.93 (d, J=1.9 Hz, 1H),8.66-8.78 (m, 1H), 9.39 (d, J=8.4 Hz, 1H), 10.97 (s, 1H).

Example 297

Example 297 was prepared using a procedure similar to that used toprepare Example 151. ESI-MS m/z: 552.2 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆)δ 1.18 (s, 6H), 3.25 (d, J=5.2 Hz, 2H), 4.66 (s, 1H), 5.20 (d, J=8.3 Hz,1H), 7.20-7.40 (m, 3H), 7.40-7.62 (m, 6H), 7.67 (ddd, J=8.5, 7.1, 1.7Hz, 1H), 7.92 (t, J=5.2 Hz, 1H), 8.21 (dd, J=1.8, 0.8 Hz, 1H), 9.48 (d,J=8.4 Hz, 1H), 10.99 (s, 1H).

Example 298

Example 298 Step a

A solution of 1H-benzo[d]imidazole-2-carboxylic acid (500 mg, 3.086mmol), 1-bromo-2-methoxyethane (852 mg, 6.17 mmmol) and CS₂CO₃ (3.02 g,9.258 mmol) in DMF (5 mL) was stirred for 3 hours at 60° C. It wasdiluted with water, extracted with EA (×3), washed with brine (×2), theorganic layer was dried, concentrated to give 750 mg (crude) of desiredcompound as yellow oil, which was used directly in the next step. ESI-MSm/z: 279.3 [M+H]⁺.

Example 298 Step b

Example 298 was prepared using a procedure similar to that used toprepare Example 152 where 2-methoxyethyl1-(2-methoxyethyl)-1H-benzo[d]imidazole-2-carboxylate was used in placeof ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI-MS m/z: 494.4[M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 3.16 (s, 3H), 3.72 (m, 2H), 4.85 (m,2H), 5.23 (d, J=7.5 Hz, 1H), 7.23-7.42 (m, 5H), 7.43-7.61 (m, 3H),7.64-7.82 (m, 3H), 9.47-9.64 (m, 1H), 11.01 (s, 1H).

Example 299

Example 299 was prepared using a procedure similar to that used toprepare Example 151 where3-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-5-fluoropicolinic acid, whichwas prepared similarly to 5-fluoro-3-morpholinopicolinic acid in Example136, was used in place of 6-fluoro-2-morpholinonicotinic acid. ESI-MSm/z: 526.5 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 1.71 (m, 2H), 1.92-2.11(m, 2H), 2.94 (m, 4H), 4.28 (s, 2H), 5.17 (d, 1H), 7.17-7.78 (m, 10H),8.30 (m, 1H), 9.19 (d, 1H), 10.96 (s, 1H).

Example 300

Example 300 Step a

To a stirred solution of methyl 4-bromo-2-hydroxybenzoate (1.5 g, 6.49mmol), KI (108 mg, 0.65 mmol) and K₂CO₃ (2.69 g, 19.47 mmol) in DMF (30mL) was added 1-bromo-2-methyloethane (902 mg, 6.49 mmol). The mixturewas heated to 80° C. overnight and water was added (150 mL). The mixturewas extracted with EA (150 mL×3) and the combined organic phase waswashed with water, brine and dried over anhydrous Na₂SO₄ andconcentrated. The residue was purified by silica gel chromatography(PE/EA=5/1) to give the desired compound as a yellow solid (1.7 g, 90%).ESI-MS m/z: 289.1 [M+H]⁺.

Example 300 Step b

To a stirred solution of the compound from step a (1.7 g, 5.88 mmol) andZn(CN)₂ (1.36 g, 11.76 mmol) in DMF (30 mL) was added Pd(PPh₃)₄ (1.36 g,1.18 mmol). The mixture was heated to 120° C. for 2 hours under N₂Atmosphere. The mixture was cooled to rt and sat FeSO₄ solution wasadded. The mixture was extracted with EA (100 mL×3) and the combinedorganic phase was washed with water, brine and dried over anhydrousNa₂SO4 and concentrated. The residue was purified by gel chromatographyto give the title compound as a white solid (1.2 g, 78%). ESI-MS m/z:263.0 [M+H]⁺.

Example 300 Step c

Example 300 was prepared using a procedure similar to that used toprepare Example 152 where methyl 4-cyano-2-(2-methoxyethoxy)benzoate wasused in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI-MSm/z: 495.2 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 3.27 (s, 3H), 3.67 (dd,J=5.5, 3.7 Hz, 2H), 4.28 (dd, J=5.5, 3.8 Hz, 2H), 5.17 (d, J=8.0 Hz,1H), 7.18-7.59 (m, 9H), 7.58-7.77 (m, 2H), 7.87 (d, J=8.0 Hz, 1H), 9.20(d, J=8.4 Hz, 1H), 10.97 (s, 1H).

Example 301

Example 301 was prepared using a procedure similar to that used toprepare Example 151 where (R)-5-cyano-3-(3-methylmorpholino)picolinicacid, which was prepared similarly to 5-cyano-3-morpholinopicolinic acidin Example 140, in place of 6-fluoro-2-morpholinonicotinic acid. ESI-MSm/z: 521.4 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 0.81 (d, J=6.3 Hz, 3H),2.65-2.76 (m, 1H), 3.40-3.51 (m, 3H), 3.54-3.68 (m, 1H), 3.78 (m, 2H),5.20 (d, J=8.3 Hz, 1H), 7.23-7.38 (m, 3H), 7.41-7.58 (m, 5H), 7.67 (m,1H), 8.26 (d, J=1.8 Hz, 1H), 8.78 (d, J=1.7 Hz, 1H), 9.41 (d, J=8.5 Hz,1H), 10.98 (s, 1H).

Example 302

Example 302 was prepared using a procedure similar to that used toprepare Example 136 where dimethylamine and ethyl3-chloro-5-(trifluoromethyl)picolinate were used in place of morpholineand ethyl 3,5-difluoropicolinate, respectively. ESI-MS m/z: 508.3[M+H]⁺.

Example 303

Example 303 was prepared using a procedure similar to that used toprepare Example 136 where 3-aminopropanenitrile and ethyl3-chloro-5-(trifluoromethyl)picolinate were used in place of morpholineand ethyl 3,5-difluoropicolinate, respectively. ESI-MS m/z: 533.2[M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 2.85 (t, J=6.5 Hz, 2H), 3.74 (q,J=6.4 Hz, 2H), 5.20 (d, J=8.3 Hz, 1H), 7.22-7.60 (m, 8H), 7.61-7.78 (m,2H), 7.89 (t, J=6.2 Hz, 1H), 8.27-8.34 (m, 1H), 9.51 (d, J=8.4 Hz, 1H),11.00 (s, 1H).

Example 304

Example 304 was prepared using a procedure similar to that used toprepare Example 151 where3-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-5-cyanopicolinic acid, which wasprepared similarly to 5-cyano-3-morpholinopicolinic acid in Example 140,in place of 6-fluoro-2-morpholinonicotinic acid. ESI-MS m/z: 533.4[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 1.71 (s, 2H), 2.07-2.11 (m, 2H),2.94-3.05 (m, 4H), 4.30 (s, 2H), 5.19-5.21 (d, J=8.0, 1H), 7.26-7.36 (m,3H), 7.44-7.55 (m, 5H), 7.65-7.69 (m, 1H), 8.11 (s, 1H), 8.68-8.69 (d,J=4.0, 1H), 9.40-9.42 (d, J=8.0, 1H), 11.00 (s, 1H).

Example 305

Example 305 was prepared using a procedure similar to that used toprepare Example 136 where 2-methoxyethan-1-amine and ethyl3-chloro-5-(trifluoromethyl)picolinate were used in place of morpholineand ethyl 3,5-difluoropicolinate, respectively. ESI-MS m/z: 538.5[M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 3.28 (s, 3H), 3.52 (m, 2H), 3.58 (m,2H), 5.20 (d, 1H), 7.22-7.40 (m, 3H), 7.40-7.60 (m, 6H), 7.68 (m, 1H),7.82 (m, 1H), 8.22-8.28 (s, 1H), 9.50 (d, 1H), 11.00 (s, 1H).

Example 306

Example 306 was prepared using a procedure similar to that used toprepare Example 298 where 1H-imidazole-2-carboxylic acid was used inplace of 1H-benzo[d]imidazole-2-carboxylic acid. ESI-MS m/z: 444.3[M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 3.20 (s, 3H), 3.63 (m, 2H), 4.54 (m,2H), 5.15 (d, J=8.4 Hz, 1H), 7.10 (d, J=1.1 Hz, 1H), 7.21-7.38 (m, 2H),7.40-7.57 (m, 5H), 7.67 (m, 1H), 9.29 (d, J=8.5 Hz, 1H), 10.98 (s, 1H).

Example 307

Example 307 was prepared using a procedure similar to that used toprepare Example 136 where methylamine and ethyl3-chloro-5-(trifluoromethyl)picolinate were used in place of morpholineand ethyl 3,5-difluoropicolinate, respectively. ESI-MS m/z: 494.3[M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 2.97 (s, 3H), 5.18 (d, J=8.3 Hz,1H), 7.13-7.82 (m, 11H), 8.22 (d, J=1.9 Hz, 1H), 9.47 (d, J=8.4 Hz, 1H),11.00 (s, 1H).

Example 308

Example 308 was prepared using a procedure similar to that used toprepare Example 136 where 2-methoxy-N-methylethan-1-amine and ethyl3-chloro-5-(trifluoromethyl)picolinate were used in place of morpholineand ethyl 3,5-difluoropicolinate, respectively. ESI-MS m/z: 566.3[M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 1.04 (s, 6H), 2.85 (s, 3H), 3.31 (d,J=2.2 Hz, 2H), 4.39 (s, 1H), 5.20 (d, J=8.5 Hz, 1H), 7.20-7.42 (m, 3H),7.41-7.61 (m, 5H), 7.68 (ddd, J=8.4, 7.1, 1.7 Hz, 1H), 7.96-8.10 (m,1H), 8.36-8.47 (m, 1H), 9.26 (d, J=8.6 Hz, 1H), 10.99 (s, 1H).

Example 309

Example 309 Step a

A solution of methyl 2-bromo-4-cyanobenzoate (480 mg, 2.0 mmol),thiophen-3-ylboronic acid (307 mg, 2.4 mmol), Pd(dppf)Cl₂ (146 mg, 0.2mmol) and K₂CO₃ (552 mg, 4.0 mmol) in dioxane (10 mL) and H₂O (2 mL) wasstirred for 1 hour at 80° C. Extracted with EA (3×), dried Na₂SO₄, andfiltered to give desired compound as a brown solid (389 mg, 80%). ESI-MSm/z: no signal.

Example 309 Step b

Example 309 was prepared using a procedure similar to that used toprepare Example 152 where methyl 4-cyano-2-(thiophen-3-yl)benzoate wasused in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI-MSm/z: 503.3 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 4.96 (m, 1H), 6.98-7.07(m, 1H), 7.24-7.80 (m, 1H), 7.90-8.06 (m, 3H), 9.11 (m, 1H), 10.96 (s,1H).

Example 310

Example 310 was prepared using a procedure similar to that used toprepare Example 152 where ethyl1-(2-methoxyethyl)-1H-pyrazole-5-carboxylate was used in place of ethyl2-morpholino-4-(trifluoromethyl)benzoate. ESI-MS m/z: 444.3 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 3.16 (s, 3H), 3.69 (m, 2H), 4.67 (m, 2H), 5.15(d, J=8.4 Hz, 1H), 6.73 (d, J=2.0 Hz, 1H), 7.20-7.39 (m, 3H), 7.41-7.59(m, 5H), 7.59-7.73 (m, 2H), 9.27 (d, J=8.4 Hz, 1H), 11.00 (s, 1H).

Example 311

Example 311 Step a

A solution of 5-bromo-3-fluoropicolinic acid (1.0 g, 4.57 mmol) wasdissolved in DMF (15 mL) and BocNHNH₂ (1.2 g, 9.14 mmol) was added. HATU(1.8 g, 4.80 mmol) and Et₃N (5 mL) was added. The mixture was stirred atrt for 1 hour. Water (20 mL) was added and the mixture was extractedwith EA (25 mL×3). The combined organic phase was dried over anhydrousNa₂SO₄ and concentrated. The residue was purified by silica gelchromatography (PE/EA=3/1) to give the desired product as a white solid(1.3 g, 83%).

Example 311 Step b

A solution of the compound from step a (1.3 g, 3.78 mmol), morpholine(658 mg, 7.56 mmol) and K₂CO₃ (1.3 g, 9.45 mmol) in DMSO (10 mL) wasstirred for overnight at 100° C. It was diluted with H₂O, and extractedwith EA (×3) and washed with brine (×2). The organic layers was combinedand concentrated to give 1.2 g (81%) white product. ESI-MS m/z: 401.2[M+H]⁺.

Example 311 Step c

A solution of the compound from step b (500 mg, 1.25 mmol) andethynyltrimethylsilane (368 mg, 3.75 mmol) in i-Pr₂NH (6 mL) was addedPd(PPh₃)₂Cl₂ (88 mg, 0.13 mmol) and CuI (24 mg, 0.13 mmol). The mixturewas heated to 80° C. for 3 hours and then cooled to r.t. It was filteredand concentrated, then purified by reverse phase C18 columnchromatography (MeCN/H₂O) to give the desired product as a yellow solid(451 mg, 86%). ESI-MS m/z: 419.4 [M+H]⁺.

Example 311 Step d

A solution of the compound from step c (451 mg, 1.08 mmol) and K₂CO₃(298 mg, 2.16 mmol) in MeOH (10 mL) was stirred at rt for 1 hour. It waspurified by Silica gel column (PE/EA=3:1-1:1) to give tert-butyl2-(5-ethynyl-3-morpholinopicolinoyl)hydrazine-1-carboxylate as a yellowsolid (348 mg, 93%). ESI-MS m/z: 347.3 [M+H]⁺.

Example 311 Step e

Example 311 was prepared using a procedure similar to that used toprepare Example 151 where tert-butyl2-(5-ethynyl-3-morpholinopicolinoyl)hydrazine-1-carboxylate was used inplace of 6-fluoro-2-morpholinonicotinohydrazide. ESI-MS m/z: 506.4[M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 2.99 (d, 4H), 3.70 (d, 4H), 4.61 (s,1H), 5.19 (d, 1H), 7.16-7.39 (m, 3H), 7.39-7.60 (m, 4H), 7.59-7.73 (m,2H), 8.41 (d, 1H), 9.28 (d, J=8.6 Hz, 1H), 10.97 (s, 1H).

Example 312

Example 312 Step a

A solution of 5-bromo-3-fluoropicolinic acid (4.0 g, 18.26 mmol) andH₂SO₄ (10 mL) in EtOH (25 mL) was heated to 80° C. for overnight andthen cooled to rt. It was concentrated, diluted with H₂O, and extractedwith EA (×3) and washed with brine (×2). The organic layers was combinedand concentrated to give desired compound as yellow oil (4.45 g, 95%).ESI-MS m/z: 247.8 [M+H]⁺.

Example 312 Step b

A solution of the compound from step a (4.45 g, 18.02 mmol) and K₂CO₃(7.46 g, 54.06 mmol) in morpholine (20 mL) was stirred at rt for 1 hour.It was concentrated, diluted with H₂O, and extracted with EA (×3) andwashed with brine (×2). The organic layers was combined andconcentrated, then purified by silica gel column (PE/EA=5:1) to givedesired compound as a yellow solid (4.79 g, 85%). ESI-MS m/z: 315.2[M+H]⁺.

Example 312 Step c

A solution of the compound from step b (1.5 g, 3.18 mmol),cyclohexenylboronic acid (481 mg, 3.82 mmol), K₂CO₃ (878 mg, 6.36 mmol)and Pd(PPh₃)₄ (367 mg, 0.318 mmol) in DMF (8 mL) was stirred forovernight. It was filtered and purified by Prep-HPLC (MeCN/H₂O) to giveethyl 5-(cyclohex-1-en-1-yl)-3-morpholinopicolinate as a yellow oil (440mg, 44%). ESI-MS m/z: 317.3 [M+H]⁺.

Example 312 Step d

Example 312 was prepared using a procedure similar to that used toprepare Example 152 where ethyl5-(cyclohex-1-en-1-yl)-3-morpholinopicolinate was used in place of ethyl2-morpholino-4-(trifluoromethyl)benzoate. ESI-MS m/z: 562.3 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 1.51-1.67 (m, 2H), 1.67-1.84 (m, 2H), 2.22 (s,2H), 2.43 (s, 2H), 2.84-3.13 (m, 4H), 3.70 (d, 4H), 5.18 (d, 1H),6.36-6.51 (m, 1H), 7.23-7.40 (m, 3H), 7.41-7.57 (m, 6H), 7.67 (m, 1H),8.41 (d, 1H), 9.15 (d, 1H), 10.95 (s, 1H).

Example 313

Example 313 Step a

A solution of ethyl 5-(cyclohex-1-en-1-yl)-3-morpholinopicolinate fromExample 312 step c (460 mg, 1.45 mmol) and Pd—C (100 mg) in 10 mL MeOHwas stirred at room temperature for 3 hrs under H₂. Pd/C was filteredoff and the filtrate was concentrated to afford ethyl5-cyclohexyl-3-morpholinopicolinate as yellow oil (500 mg). ESI-MS m/z:319.3 [M+H]⁺.

Example 313 Step b

Example 313 was prepared using a procedure similar to that used toprepare Example 152 where ethyl 5-cyclohexyl-3-morpholinopicolinate wasused in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI-MSm/z: 564.3 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 1.39 (m, 5H), 1.76 (m,5H), 2.52-2.71 (m, 1H), 2.97 (s, 4H), 3.69 (s, 4H), 5.17 (d, J=8.6 Hz,1H), 7.32 (dd, J=18.4, 7.8 Hz, 3H), 7.40-7.61 (m, 6H), 7.67 (t, J=7.5Hz, 1H), 8.23 (d, J=1.7 Hz, 1H), 9.14 (d, J=8.6 Hz, 1H), 10.96 (s, 1H).

Example 314

Example 314 Step a

A solution of the compound methyl 5-bromo-3-morpholinopicolinate fromExample 160 step a (800 mg, 2.55 mmol), pyrrolidine (362 mg, 5.1 mmol),CuI (242 mg, 1.3 mmol), L-Proline (147 mg, 1.3 mmol) and K₂CO₃ (704 mg,5.1 mmol) in DMSO (6 mL) was stirred at rt for 2 hours. It was filteredand then purified by Prep-HPLC (MeCN/H₂O) to give ethyl3-morpholino-5-(pyrrolidin-1-yl)picolinate as a yellow oil (376 mg,48%). ESI-MS m/z: 306.2 [M+H]⁺.

Example 314 Step b

Example 314 was prepared using a procedure similar to that used toprepare Example 152 where ethyl3-morpholino-5-(pyrrolidin-1-yl)picolinate was used in place of ethyl2-morpholino-4-(trifluoromethyl)benzoate. ESI-MS m/z: 551.4 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 1.87-2.10 (m, 4H), 2.79-3.14 (m, 4H), 3.25-3.52(m, 4H), 3.70 (m, 4H), 5.16 (d, 1H), 6.52 (d, 1H), 7.24-7.32 (m, 1H),7.36 (m, 2H), 7.42-7.59 (m, 5H), 7.68 (m, 1H), 7.73 (d, 1H), 8.94 (d,1H), 10.96 (s, 1H).

Example 315

Example 315 was prepared using a procedure similar to that used toprepare Example 309 where5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one wasused in place of thiophen-3-ylboronic acid. ESI-MS m/z: 528.4 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 3.47 (s, 3H), 5.12 (d, J=8.3 Hz, 1H), 6.34 (d,J=9.3 Hz, 1H), 7.23-7.40 (m, 4H), 7.50 (m, 5H), 7.67 (m, 1H), 7.90 (d,J=2.6 Hz, 1H), 7.99 (d, J=4.0 Hz, 3H), 9.27 (d, J=8.4 Hz, 1H), 10.97 (s,1H).

Example 316

Example 316 Step a

A solution of 3-bromoisoquinolin-4-amine (980 mg, 4.4 mmol), Cs₂CO₃ (4.3g, 13.2 mmol), 1-bromo-2-(2-bromoethoxy) ethane (1.5 g, 6.7 mmol) in DMA(20 mL) was stirred at 120° C. overnight. Then H₂O (20 mL) was added tothe mixture and it was extracted with EA (×3). The organic layer wasdried and purified by reverse phase C18 column chromatography (MeCN/H₂O)to give desired compound as brown solid (500 mg, 39%). ESI-MS m/z: 293.2[M+H]⁺.

Example 316 Step b

A solution of the compound from step a (470 mg, 1.6 mmol), Pd(dppf)Cl₂(200 mg, 0.245 mmol) and TEA (2 mL) in MeOH (10 mL). The solution wasstirred for overnight at 100° C. in CO(g) under 20 atm. The solid wasfiltered out. The filtrate was concentrated under vacuum, and waspurified by reverse phase C18 column chromatography (MeCN/H₂O) to givemethyl 4-morpholinoisoquinoline-3-carboxylate as black solid (1.0 g).ESI-MS m/z: 273.3 [M+H]⁺.

Example 316 Step c

Example 316 was prepared using a procedure similar to that used toprepare Example 152 where methyl 4-morpholinoisoquinoline-3-carboxylatewas used in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate.ESI-MS m/z: 532.4 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 3.02 (d, J=6.0 Hz,4H), 3.78 (t, J=4.5 Hz, 4H), 5.22 (d, J=8.6 Hz, 1H), 7.22-7.60 (m, 8H),7.68 (ddd, J=8.4, 7.1, 1.7 Hz, 1H), 7.87 (dddd, J=32.0, 8.0, 6.9, 1.2Hz, 2H), 8.18-8.30 (m, 1H), 8.37 (d, J=8.3 Hz, 1H), 9.21 (d, J=9.6 Hz,2H), 10.99 (s, 1H).

Example 317

Example 317 Step a

A solution of methyl 4-amino-2-fluorobenzoate (1.0 g, 5.9 mmol) andK₂CO₃ (1.6 g, 11.8 mmol) in morpholine (4 mL) was heated to 100° C. forovernight and then cooled to r.t. Water (10 mL) was added and themixture was extracted with EA (10 mL×3). The combined organic phase wasdried over anhydrous Na₂SO₄ and concentrated. The residue waschromatographed (silica, PE:EA=2:1) to give desired compound as a pinksolid (990 mg, 71%). ESI-MS m/z: 237.2 [M+H]⁺.

Example 317 Step b

A solution of the compound from step a (990 mg, 4.2 mmol) and Cs₂CO₃(2.05 g, 6.3 mmol) in DMF (5 mL) was added 1,4-dibromobutane (898 mg,4.2 mmol). The mixture was heated to 80° C. for 24 hours and then cooledto rt. Water (10 mL) was added and the mixture was extracted with EA (10mL×3). The combined organic phase was washed with water (20 mL) andbrine (20 mL). It was then dried over anhydrous Na₂SO₄ and concentrated.The residue was chromatographed (silica, PE:EA=5:1) to give methyl2-morpholino-4-(pyrrolidin-1-yl)benzoate as a pink solid (200 mg, 16%).ESI-MS m/z: 291.3 [M+H]⁺.

Example 317 Step c

Example 317 was prepared using a procedure similar to that used toprepare Example 152 where methyl2-morpholino-4-(pyrrolidin-1-yl)benzoate was used in place of ethyl2-morpholino-4-(trifluoromethyl)benzoate. ESI-MS m/z: 550.3 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 1.91-2.01 (m, 4H), 2.88 (m, 4H), 3.24-3.30 (m,4H), 3.68 (m, 4H), 5.12 (d, J=8.9 Hz, 1H), 6.15 (d, J=2.2 Hz, 1H), 6.29(m, 1H), 7.24-7.41 (m, 3H), 7.41-7.57 (m, 6H), 7.66 (m, 1H), 8.80 (d,J=8.9 Hz, 1H), 10.94 (s, 1H).

Example 318

Example 318 Step a

A solution of 6-chloro-3-fluoropicolinic acid (525 mg, 3.0 mmol) andH₂SO₄ (1 mL) in EtOH (20 mL) was stirred for 2 hours at 80° C. Then itwas adjusted PH to 8-9, extracted with EA (3×), dried Na₂SO₄, filteredand concentrated to give desired compound as a white solid (610 mg,100%). ESI-MS m/z: 204.2 [M+H]⁺.

Example 318 Step b

A solution of compound from step a (406 mg, 2.0 mmol),cyclopropylboronic acid (860 mg, 10.0 mmol), Pd(dppf)Cl₂ (146 mg, 0.2mmol) and Cs₂CO₃ (978 mg, 3.0 mmol) in dioxane (20 mL) was heated to120° C. for 2 hours. Then it was poured into water and extracted with EA(3×) to give desired crude compound as brown oil. (1 g). ESI-MS m/z:209.9 [M+H]⁺.

Example 318 Step c

A solution of compound from step b (1 g, crude) in morpholine (30 mL)was stirred for 3 hours at 110° C. The solvents were removed andextracted with EA (3×) to give desired crude ethyl6-cyclopropyl-3-morpholinopicolinate as brown oil. (1.2 g). ESI-MS m/z:277.3 [M+H]⁺.

Example 318 Step d

Example 318 was prepared using a procedure similar to that used toprepare Example 152 where ethyl 6-cyclopropyl-3-morpholinopicolinate wasused in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI-MSm/z: 522.4 [M+H]⁺. ¹H NMR (300 MHz, Methanol-d₄) δ 1.01 (d, J=5.8 Hz,4H), 2.14 (m, 1H), 3.08 (m, 4H), 3.86 (m, 4H), 5.39 (s, 1H), 7.26-7.79(m, 11H).

Example 319

Example 319 was prepared using a procedure similar to that used toprepare Example 309 where furan-3-ylboronic acid was used in place ofthiophen-3-ylboronic acid. ESI-MS m/z: 487.3 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 5.09 (d, J=8.4 Hz, 1H), 6.37-6.60 (m, 1H), 7.23-7.41 (m, 3H),7.42-7.58 (m, 5H), 7.61-7.75 (m, 2H), 7.88-8.02 (m, 3H), 8.08 (d, J=1.5Hz, 1H), 9.19 (d, J=8.4 Hz, 1H), 10.98 (s, 1H).

Example 320

Example 320 was prepared using a procedure similar to that used toprepare Example 309 where (3,5-dimethylisoxazol-4-yl)boronic acid wasused in place of thiophen-3-ylboronic acid. ESI-MS m/z: 516.2 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 1.91 (d, J=3.2 Hz, 3H), 2.17 (s, 3H), 5.08 (d,J=8.1 Hz, 1H), 7.22-7.37 (m, 3H), 7.41-7.60 (m, 5H), 7.60-7.71 (m, 1H),7.98 (d, J=1.7 Hz, 1H), 8.02-8.15 (m, 2H), 9.33 (d, J=8.4 Hz, 1H), 10.98(s, 1H).

Example 321

Example 321 was prepared using a procedure similar to that used toprepare Example 169 where methyl3-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-5-bromopicolinate, preparedsimilarly to methyl 5-bromo-3-morpholinopicolinate in Example 160, wasused in place of methyl 5-bromo-3-morpholinopicolinate. ESI-MS m/z:548.2 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 1.18 (s, 2H), 1.6 (s, 2H),2.15 (d, 1H), 4.25-5.15 (m, 3H), 7.14-8.27 (m, 11H), 9.15 (d, 1H), 11.15(d, 1H).

Example 322

Example 322 was prepared using a procedure similar to that used toprepare Example 316 where 2-bromoquinolin-3-amine was used in place of3-bromoisoquinolin-4-amine. ESI-MS m/z: 532.2 [M+H]⁺. ¹H NMR (300 MHz,DMSO-d₆) δ 2.94-3.12 (m, 4H), 3.74 (m, 4H), 5.22 (d, J=7.9 Hz, 1H), 7.27(m, 1H), 7.32-7.40 (m, 2H), 7.41-7.58 (m, 5H), 7.66 (m, 3H), 7.97 (m,2H), 8.07 (s, 1H), 9.33 (d, J=8.5 Hz, 1H), 10.89 (s, 1H).

Example 323

Example 323 Step a

A solution of methyl 5-bromo-3-morpholinothiophene-2-carboxylate,prepared in Example 182 step a, (900 mg, 2.9 mmol) in THF/H₂O (10 mL/3mL) was added NaOH (1.18 mg, 29.4 mmol). The mixture was heated to 50°C. overnight. The mixture was cooled to room temperature and purified byreverse phase C18 column chromatography (MeCN/H₂O) to give the desiredcompound as a yellow oil (400 mg, 47%). ESI-MS m/z: 291.8 [M+H]⁺.

Example 323 Step b

A solution of the compound from step a (400 mg, 1.37 mmol) and BocNHNH₂(362.1 mg, 2.74 mmol) in DMF (5 mL) was added HATU (1.04 g, 2.74 mmol)and DIPEA (0.5 mL). The mixture was stirred at room temperature for 1hour. Water (5 mL) was added and the mixture was extracted with EA (20mL×3). The combined organic phase was dried over anhydrous Na₂SO₄ andconcentrated. The residue was purified by silicagel chromatography(PE/EA=10/1) to give the desired compound as a yellow oil (230 mg, 41%).ESI-MS m/z: 408.1 [M+H]⁺.

Example 323 Step c

Under N₂ atmosphere the compound from step b (230 mg, 0.57 mmol) wasdissolved in DMF (4 mL) and Pd(PP₃)₄ (131 mg, 0.11 mmol) and Zn(CN)₂(131 mg, 1.13 mmol) was added. The mixture was heated to 120° C. for 2hours. FeSO₄ solution (20 mL) was added and the mixture was extractedwith EA (20 mL×3). The combined organic phase was washed with water,dried over anhydrous Na₂SO₄ and concentrated. The residue was purifiedby silica gel chromatography (PE/EA=5/1) to give tert-butyl2-(5-cyano-3-morpholinothiophene-2-carbonyl)hydrazine-1-carboxylate as ayellow oil (128 mg, 64%). ESI-MS m/z: 353.1 [M+H]⁺.

Example 323 Step d

Example 323 was prepared using a procedure similar to that used toprepare Example 151 where tert-butyl2-(5-cyano-3-morpholinothiophene-2-carbonyl)hydrazine-1-carboxylate wasused in place of 6-fluoro-2-morpholinonicotinohydrazide. ESI-MS m/z:512.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 3.02-3.12 (m, 4H), 3.61-3.71(m, 4H), 5.13 (d, J=8.3 Hz, 1H), 7.21-7.39 (m, 3H), 7.39-7.60 (m, 5H),7.67 (ddd, J=8.5, 7.0, 1.8 Hz, 1H), 7.92 (s, 1H), 9.36 (d, J=8.4 Hz,1H), 10.99 (s, 1H).

Example 324

Example 324 Step a

A solution of 6-chloro-3-fluoropicolinic acid (1.40 g, 8 mmol),tert-butyl hydrazinecarboxylate (1.32 g, 10 mmol), DIPEA (3 mL) and HATU(3.80 g, 10 mmol) in DMF (50 mL) was stirred for 0.5 hours at 25° C.Then it was quenched with H₂O, extracted with EA (3×), dried Na₂SO₄,filtered and purified by reverse phase C18 column chromatography(MeCN/H₂O) to give desired compound as a white solid (1.74 g, 75%).ESI-MS m/z: 600.9 [2M+Na]⁺.

Example 324 Step b

A solution of compound from step a (725 mg, 2.5 mmol), Zn(CN)₂ (580 mg,5 mmol) and Pd(PPh₃)₄ (580 mg, 0.5 mmol) in DMA (20 mL) was heated to140° C. for 1 hour in the microwave. The mixture was filtered, extractedwith EA (3×), the solvents were removed and purified by reverse phaseC18 column chromatography (MeCN/H₂O) to give desired product as yellowsolid. (224 mg, 32%). ESI-MS m/z: 302.9 [M+H]⁺.

Example 324 Step c

A solution of compound from step b (224 mg, 0.8 mmol) in morpholine (10mL) was stirred for 1 hour at 80° C. The solvents were removed andpurified by reverse phase C18 column chromatography (MeCN/H₂O) to givetert-butyl 2-(6-cyano-3-morpholinopicolinoyl)hydrazine-1-carboxylate asyellow solid. (208 mg, 75%). ESI-MS m/z: 348.3 [M+H]⁺.

Example 324 Step d

Example 324 was prepared using a procedure similar to that used toprepare Example 151 where tert-butyl2-(6-cyano-3-morpholinopicolinoyl)hydrazine-1-carboxylate was used inplace of 6-fluoro-2-morpholinonicotinohydrazide. ESI-MS m/z: 507.3[M+H]⁺. H NMR (300 MHz, DMSO-d₆) δ 3.08 (m, 4H), 3.70 (m, 4H), 5.18 (s,1H), 7.20-7.58 (m, 8H), 7.67 (m, 2H), 8.01 (d, J=8.6 Hz, 1H), 9.34-9.42(m, 1H), 10.90 (s, 1H).

Example 325

Example 325 was prepared using a procedure similar to that used toprepare Example 151 where 5-cyano-3-morpholinopicolinic acid, preparedin Example 140, was used in place of 6-fluoro-2-morpholinonicotinicacid. ESI-MS m/z: 507.2 [M+H]⁺.

Example 326

Example 326 was prepared using a procedure similar to that used toprepare Example 151 where (R)-5-cyano-3-(2-methylmorpholino)picolinicacid, which was prepared similarly to 5-cyano-3-morpholinopicolinic acidin Example 140, was used in place of 6-fluoro-2-morpholinonicotinicacid. ESI-MS m/z: 521.5 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 1.08 (d,3H), δ 2.54-2.62 (d, 1H), 2.83 (m, 1H), 3.18 (m, 2H), 3.57-3.74 (m, 2H),3.74-3.89 (m, 1H), 5.21 (d, 1H), 7.25-7.42 (m, 3H), 7.43-7.59 (m, 5H),7.69 (m, 1H), 8.13 (d, 1H), 8.72 (d, 1H), 9.43 (d, 1H), 11.00 (s, 1H).

Example 327

Example 327 was prepared using a procedure similar to that used toprepare Example 160 where 1-methylpiperazine and ethyl3-chloro-5-(trifluoromethyl)picolinate were used in place of morpholineand methyl 5-bromo-3-fluoropicolinate, respectively. ESI-MS m/z: 563.2[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 2.19 (s, 3H), 2.49-2.50 (m, 4H),3.05 (s, 4H), 5.19-5.21 (d, J=8.0, 1H), 7.28-7.37 (m, 8H), 7.44-7.54 (m,1H), 7.66-7.85 (m, 1H), 8.65 (s, 1H), 9.35-9.37 (d, J=8.0, 1H), 10.99(s, 1H).

Example 328

Example 328 was prepared using a procedure similar to that used toprepare Example 160 where piperidin-4-ol and ethyl3-chloro-5-(trifluoromethyl)picolinate were used in place of morpholineand methyl 5-bromo-3-fluoropicolinate, respectively. ESI-MS m/z: 564.2[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 1.54-1.61 (m, 2H), 1.79-1.82 (m,2H), 2.82-2.87 (m, 2H), 3.21-3.24 (m, 2H), 3.60-3.65 (m, 1H), 4.66-4.67(d, J=4.0, 1H), 5.19-5.21 (d, J=4.0, 1H), 7.26-7.30 (m, 1H), 7.34-7.37(m, 2H), 7.44-7.55 (m, 5H), 7.65-7.66 (m, 1H), 7.67-7.69 (m, 1H), 8.61(s, 1H), 9.31-9.33 (d, J=8.0, 1H), 10.97 (s, 1H).

Example 329

Example 329 was prepared using a procedure similar to that used toprepare Example 151 where (S)-5-cyano-3-(2-methylmorpholino)picolinicacid, which was prepared similarly to 5-cyano-3-morpholinopicolinic acidin Example 140, was used in place of 6-fluoro-2-morpholinonicotinicacid. ESI-MS m/z: 521.4 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 1.08 (d,3H), 2.54-2.64 (m, 1H), 2.71-2.93 (m, 1H), 3.19 (m, 2H), 3.61-3.91 (m,3H), 5.22 (d, 1H), 7.22-7.41 (m, 3H), 7.43-7.61 (m, 5H), 7.69 (m, 1H),8.13 (d, 1H), 8.72 (d, 1H), 9.43 (d, 1H), 11.00 (s, 1H).

Example 330

Example 330 Step a

To a stirred solution of the ethyl2-amino-5-methylthiophene-3-carboxylate (2.0 g, 10.8 mmol) in DMA (20mL) was added 1-bromo-2-(2-bromoethoxy) ethane (5.42 g, 27.5 mmol),Cs₂CO₃ (11.4 g, 35 mmol) at rt. The mixture was refluxed overnight at80° C. The mixture was cooled to rt, and then poured into water andextracted with EA (3*100 ml). The organic layer was dried over Na₂SO₄.The residue was purified by silica gel chromatography (PE/EA=4/1) togive the ethyl 5-methyl-2-morpholinothiophene-3-carboxylate as a whitesolid (700 mg, 28%). ESI-MS m/z: 256.2 [M+H]⁺.

Example 330 Step b

Example 330 was prepared using a procedure similar to that used toprepare Example 152 where ethyl5-methyl-2-morpholinothiophene-3-carboxylate was used in place of ethyl2-morpholino-4-(trifluoromethyl)benzoate. ESI-MS m/z: 501.0 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ2.38 (3H, d), 2.97 (4H, dd), 3.32 (4H, m), 5.12(1H, d), 6.90 (1H, d), 7.44 (9H, m), 8.96 (1H, d), 10.96 (1H, s).

Example 331

Example 331 Step a

A solution of the compound ethyl 3-chloro-5-(trifluoromethyl)picolinate(3.8 g, 15 mmol) and PMBNH₂ (4.94 g, 36 mol) in DMSO (50 mL) was stirredfor 18 hours at 110° C. It was purified by reverse phase C18 columnchromatography (MeCN/H₂O) to give desired compound as a light yellowsolid (1.4 g, 27%).

Example 331 Step b

A solution of the compound from step a (1.06 g, 3 mmol) and TFA (5 mL)in DCM (20 mL) was stirred for 1 hour at rt. The crude product waspurified by reverse phase C18 column chromatography (MeCN/H₂O) to givedesired compound as a light yellow solid (585 mg, 83%). ESI-MS m/z:235.2 [M+H]⁺.

Example 331 Step c

A solution of the compound from step b (421 mg, 1.8 mmol), TMSCN (1.78g, 18 mmol) and (CH₂O)_(n) (540 mg, 18 mmol) in MeCN (15 mL) was stirredfor 18 hours at 90° C. The crude product was purified by reverse phaseC18 column chromatography (MeCN/H₂O) to ethyl3-((cyanomethyl)amino)-5-(trifluoromethyl)picolinate as a brown oil.(328 mg, 67%). ESI-MS m/z: 274.2 [M+H]⁺.

Example 331 d

Example 331 was prepared using a procedure similar to that used toprepare Example 152 where ethyl3-((cyanomethyl)amino)-5-(trifluoromethyl)picolinate was used in placeof ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI-MS m/z: 519.4[M+H]⁺. H NMR (300 MHz, DMSO-d₆) δ 4.76 (d, J=6.4 Hz, 2H), 5.23 (s, 1H),7.19-7.61 (m, 8H), 7.63-7.83 (m, 2H), 8.03 (m, 1H), 8.46 (m, 1H), 9.56(s, 1H), 10.96 (s, 1H).

Example 332

Example 332 Step a

A solution of tert-butyl2-(5-bromo-3-morpholinopicolinoyl)hydrazine-1-carboxylate, prepared inExample 311 step b, (2.0 g, 6.0 mmol) was dissolved in DMSO (20 mL),then morpholine (1.04 g, 12.0 mmol) and K₂CO₃ (2.48 g, 18.0 mmol) wasadded. The mixture was stirred at rt overnight. It was concentrated,diluted with H₂O, and extracted with EA (×3) and washed with brine (×2).The organic layers was combined and concentrated, then purified byreverse phase C18 column chromatography (MeCN/H₂O) to give desiredcompound as a light gray solid (1.96 g, 82%). ESI-MS m/z: 401.1 [M+H]⁺.

Example 332 Step b

A solution of the compound from step a (700 mg, 1.8 mmol) was dissolvedin 1-methylpyrrolidin-2-one (6 mL), then NaSCH₃ (245 mg, 3.5 mmol) andK₂CO₃ (725 mg, 5.3 mmol) was added. The mixture was stirred at r.t. forovernight. Water (10 mL) was added and purified by reverse phase C18column chromatography (MeCN/H₂O) to give the desired product as a brownsolid (515 mg, 80%). ESI-MS m/z: 369.1 [M+H]⁺.

Example 332 Step c

A solution of the compound from step b (495 mg, 1.4 mmol) and Oxone(1.22 g, 2.0 mmol) in MeOH (3 mL), acetone (3 mL) and H₂O (3 mL) wasstirred for three hours at rt. It was concentrated, and extracted withEA (×3) and washed with brine (×2). The organic layers were combined andconcentrated to give 254 mg (47%) of tert-butyl2-(5-(methylsulfonyl)-3-morpholinopicolinoyl)hydrazine-1-carboxylate asa yellow product. ESI-MS m/z: 401.2 [M+H]⁺.

Example 332

Example 332 was prepared using a procedure similar to that used toprepare Example 151 where tert-butyl2-(5-(methylsulfonyl)-3-morpholinopicolinoyl)hydrazine-1-carboxylate wasused in place of 6-fluoro-2-morpholinonicotinohydrazide. ESI-MS m/z:560.5 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 3.09 (s, 4H), 3.39 (s, 3H),3.75 (s, 4H), 5.22 (d, 1H), 7.29 (d, 1H), 7.33-7.40 (m, 2H), 7.41-7.60(m, 5H), 7.63-7.75 (m, 1H), 7.98 (d, 1H), 8.76 (d, 1H), 9.44 (d, 1H),10.99 (s, 1H).

Example 333

Example 333 was prepared using a procedure similar to that used toprepare Example 151 where3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5-cyanopicolinic acid, which wasprepared similarly to 5-cyano-3-morpholinopicolinic acid in Example 140,was used in place of 6-fluoro-2-morpholinonicotinic acid. ESI-MS m/z:533.5 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 1.86 (s, 4H), 3.49 (m, 2H),3.80 (m, 2H), 3.84-3.97 (d, 2H), 5.21 (d, 1H), 7.23-7.40 (m, 3H),7.40-7.60 (m, 5H), 7.68 (m, 1H), 8.04 (d, 1H), 8.58 (d, 1H), 9.39 (d,1H), 11.00 (s, 1H).

Example 334

Example 334 was prepared using a procedure similar to that used toprepare Example 272 where methyl 4-bromo-1,2,5-thiadiazole-3-carboxylatewas used in place of methyl 2-methyl-5-bromothiazole-4-carboxylate.ESI-MS m/z: 560.5 [M+H]⁺.

Example 335

Example 335 Step a

A solution of ethyl 5-amino-2-methylthiazole-4-carboxylate (1.7 g, 9.0mmol), 1-bromo-2-methoxyethane (1.2 g, 9.0 mmol) and Cs₂CO₃ (4.4 g, 13.5mmol) in DMF (10 mL) was heated to 50° C. for 7 hours and then cooled tor.t. The crude product was purified by reverse phase C18 columnchromatography (MeCN/H₂O) to give ethyl5-((2-methoxyethyl)amino)-2-methylthiazole-4-carboxylate as an orangeoil (850 mg, 3.48 mmol, 39%). ESI-MS m/z: 245.2 [M+H]⁺.

Example 335 Step b

Example 335 was prepared using a procedure similar to that used toprepare Example 152 where ethyl5-((2-methoxyethyl)amino)-2-methylthiazole-4-carboxylate was used inplace of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI-MS m/z:490.3 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 2.52 (s, 3H), 3.27 (s, 3H),3.38 (d, J=5.4 Hz, 2H), 3.52 (m, 2H), 5.11 (d, J=8.7 Hz, 1H), 6.84 (m,1H), 7.22-7.37 (m, 3H), 7.40-7.58 (m, 5H), 7.67 (m, 1H), 8.89 (d, J=8.7Hz, 1H), 10.95 (s, 1H).

Example 336

Example 336 Step a

In an oven-dried vial, methyl 5-bromothiazole-4-carboxylate (200 mg,0.90 mmol) was dissolved in MeCN (2.4 mL). Morpholine (87 uL, 0.99 mmol)and DBU (0.2 mL, 1.35 mmol) were added to the vial sequentially. Thevial was sealed and heated to 80° C. for 5 hours. Cool the vial to roomtemperature and quench with water. Extract aqueous layer (3×) withEtOAc. The organic layer was dried with Na₂SO₄, filtered andconcentrated. The crude product was purified on silica gel(hexane/EtOAc: 0% to 80%), affording methyl5-morpholinothiazole-4-carboxylate (120 mg, 58%) as a white solid. ESIMS m/z=229.1 [M+H]⁺.

Example 336 Step b

Example 336 was prepared using a procedure similar to that used toprepare Example 152 where methyl 5-morpholinothiazole-4-carboxylate wasused in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI MSm/z=488.1537 [M+H]⁺.

Example 337

Example 337 was prepared using a procedure similar to that used toprepare Example 272 where ethyl 5-bromooxazole-4-carboxylate was used inplace of methyl 2-methyl-5-bromothiazole-4-carboxylate. ESI MS m/z=486.2[M+H]⁺.

Example 338

Example 338 Step a

To an oven-dried vial, methyl 5-morpholinothiazole-4-carboxylate,prepared in Example 336, (247 mg, 1.08 mmol) was dissolved in MeCN (5.4mL). NBS (208 mg, 1.17 mmol) was added to the vial in one portion atroom temperature. The reaction was allowed to stir at room temperatureuntil the starting material was consumed. The reaction mixture wasconcentrated and purified on silica gel (hexane/EtOAc: 0% to 80%),affording methyl 2-bromo-5-morpholinothiazole-4-carboxylate (256 mg,77%) as a white solid. ESI MS m/z=309.0 [M+H]⁺.

Example 338 Step b

To a vial, add methyl 2-bromo-5-morpholinothiazole-4-carboxylate (212mg, 0.69 mmol), cyclopropylboronic acid (65 mg, 0.76 mmol), K₂CO₃ (286mg, 2.07 mmol) and Pd(PPh₃)₄ (40 mg, 0.04 mmol). The vial was sealed andevacuated with nitrogen. Toluene (2.9 mL) and water (0.6 mL) were addedto the vial with a syringe. The reaction mixture was heated to 80° C.and stirred at that temperature for 20 hours. The vial was cooled toroom temperature and quenched with water. The aqueous layer wasextracted (3×) with EtOAc. The organic layer was dried with NaSO₄,filtered and concentrated. The crude product was added to a silica gelcolumn and was eluted with ethyl acetate/hexane 0% to 100% to givemethyl 2-cyclopropyl-5-morpholinothiazole-4-carboxylate (76 mg, 41%) asa solid.

Example 338 Step c

Example 338 was prepared using a procedure similar to that used toprepare Example 152 where methyl2-cyclopropyl-5-morpholinothiazole-4-carboxylate was used in place ofethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI MS m/z=528.4 [M+H]⁺.¹H NMR (300 MHz, DMSO-d₆) δ 0.72-1.00 (m, 2H), 1.08 (m, 2H), 2.33 (m,1H), 2.82-3.16 (m, 4H), 3.54-3.90 (m, 4H), 5.14 (d, J=8.3 Hz, 1H),7.22-7.41 (m, 3H), 7.41-7.60 (m, 5H), 7.67 (m, 1H), 9.07 (d, J=8.4 Hz,1H), 10.97 (s, 1H).

Example 339

Example 339 was prepared using a procedure similar to that used toprepare Example 272 where ethyl5-bromo-2-(trifluoromethyl)thiazole-4-carboxylate was used in place ofmethyl 2-methyl-5-bromothiazole-4-carboxylate. ESI-MS m/z: 556.1 [M+H]⁺.

Example 340

Example 340 was prepared using a procedure similar to that used toprepare Example 338 where phenylboronic acid was used in place ofcyclopropylboronic acid. ESI MS m/z=564.1823 [M+H]⁺.

Example 341

Example 341 Step a

To an oven-dried vial, methyl 2-bromo-5-chlorothiazole-4-carboxylate(200 mg, 0.78 mmol) and Pd(Ph₃P)₄ (90 mg, 0.08 mmol) were added. Thevial was sealed and evacuated and refilled with nitrogen (3×). To thesealed vial, THF (3.9 mL) and pyridin-2-ylzinc(II) bromide (1.9 mL, 0.94mmol) were added sequentially. The vial was heated to 65° C. overnight.The reaction mixture was allowed to cool and then diluted with water andEtOAc. The aqueous layer was extracted twice with EtOAc. The organiclayer was dried with Na₂SO₄, filtered and concentrated. The crudeproduct was added to a silica gel column and was eluted with ethylacetate/hexane 0% to 100% to give methyl5-chloro-2-(pyridin-2-yl)thiazole-4-carboxylate (106 mg, 53% yield) as asolid. ESI MS m/z=255.0 [M+H]⁺.

Example 341 Step b

Example 341 was prepared using a procedure similar to that used toprepare Example 272 where methyl5-chloro-2-(pyridin-2-yl)thiazole-4-carboxylate was used in place ofmethyl 2-methyl-5-bromothiazole-4-carboxylate. ESI MS m/z=565.3 [M+H]⁺.

Example 342

Example 342 Step a

To a vial, add methyl 2-bromo-5-chlorothiazole-4-carboxylate (200 mg,0.78 mmol), (2-methoxyphenyl)boronic acid (142 mg, 0.94 mmol), Pd(Ph₃P)₄(90 mg, 0.08 mmol) and K₂CO₃ (323 mg, 2.34 mmol). The vial was sealedand evacuated with nitrogen (3×). Toluene (3.2 mL) and water (650 μL)were added to the sealed vial. The vial was heated to 80° C. and stirredovernight. The reaction mixture was diluted with water and EtOAc. Theaqueous layer was extracted twice with EtOAc. The organic layer wasdried with Na₂SO₄, filtered and concentrated. The crude product wasadded to a silica gel column and was eluted with ethyl acetate/hexane 0%to 50% to give methyl 5-chloro-2-(2-methoxyphenyl)thiazole-4-carboxylate(150 mg, 68% yield) as a white solid. ESI MS m z=284.0 [M+H]⁺.

Example 342 Step b

Example 342 was prepared using a procedure similar to that used toprepare Example 272 where methyl5-chloro-2-(2-methoxyphenyl)thiazole-4-carboxylate was used in place ofmethyl 2-methyl-5-bromothiazole-4-carboxylate. ESI MS m/z=594.3 [M+H]⁺.

Example 343

Example 343 was prepared using a procedure similar to that used toprepare Example 152 where ethyl 2-methylthiazole-4-carboxylate was usedin place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI MSm/z=417.1 [M+H]⁺.

Example 344

Example 344 Step a

To an oven-dried vial, ethyl 2-methylthiazole-4-carboxylate (1.0 g, 5.84mmol) was dissolved in DMF (29 mL) open to air to give a yellowsolution. 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione (1.1 g, 4.67mmol) was added to the solution and stirred overnight at roomtemperature. The reaction mixture was diluted with water and extractedwith EtOAc. The organic layer was dried with NaSO₄, filtered andconcentrated. The crude product was added to a silica gel column and waseluted with ethyl acetate/hexane 0% to 20% to give ethyl5-chloro-2-methylthiazole-4-carboxylate (257 mg, 21% yield) as an oil.ESI MS m/z=206.0 [M+H]⁺.

Example 344

Example 344 was prepared using a procedure similar to that used toprepare Example 152 where ethyl 5-chloro-2-methylthiazole-4-carboxylatewas used in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESIMS m/z=451.1 [M+H]⁺.

Example 345

Example 345 Step a

To an oven-dried vial, methyl 5-bromo-2-methylthiazole-4-carboxylate(600 mg, 2.54 mmol),2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(587 mg, 2.80 mmol), K₃PO₄.H₂O (1.5 g, 6.61 mmol), and SPhos Pd G3 (66mg, 0.08 mmol) were dissolved in DMF (4.4 ml) and water (436 μl) undernitrogen to give a yellow suspension. The resulting mixture was heatedat 100° C. for 24 hours. The reaction mixture was cooled to roomtemperature and diluted with EtOAc. The aqueous layer was extracted withEtOAc (2×10 mL). The organic layer was dried with Na₂SO₄, filtered andconcentrated. The crude product was added to a silica gel column and waseluted with ethyl acetate/hexane 0% to 40% to give methyl5-(3,6-dihydro-2H-pyran-4-yl)-2-methylthiazole-4-carboxylate (170 mg,28% yield) as a white solid.

Example 345 Step b

Example 345 was prepared using a procedure similar to that used toprepare Example 152 where methyl5-(3,6-dihydro-2H-pyran-4-yl)-2-methylthiazole-4-carboxylate was used inplace of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI MSm/z=499.2 [M+H]⁺.

Example 346

To a round-bottomed flask,(S)-3-((5-(5-(3,6-dihydro-2H-pyran-4-yl)-2-methylthiazol-4-yl)-1,3,4-oxadiazol-2-yl)amino)-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one(Example 345) (23 mg, 0.05 mmol) was dissolved in MeOH (2 mL) to give aclear solution. Palladium on carbon (5 mg, 0.05 mmol) was added to thereaction mixture in one portion. The flask was sealed and evacuated witha hydrogen balloon. The reaction was stirred under hydrogen overnight.The reaction mixture was filtered through celite, washed with EtOAc, andconcentrated, affording(S)-3-((5-(2-methyl-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)-1,3,4-oxadiazol-2-yl)amino)-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one(17 mg, 74% yield) as a white solid. ESI MS m/z=501.2 [M+H]⁺.

Example 347

Example 347 was prepared using a procedure similar to that used toprepare Example 345 where methyl 5-bromothiazole-4-carboxylate was usedin place of methyl 5-bromo-2-methylthiazole-4-carboxylate. ESI MSm/z=485.1 [M+H]⁺.

Example 348

Example 348 Step a

In an oven-dried round-bottomed flask, potassium iodide (706 mg, 4.25mmol), potassium carbonate (588 mg, 4.25 mmol), and methyl3-aminofuran-2-carboxylate (300 mg, 2.13 mmol) were dissolved in DMA(6.0 mL) under nitrogen to give a clear suspension. The flask was sealedand 1-bromo-2-(2-bromoethoxy)ethane (542 mg, 2.34 mmol) was added to thereaction mixture via syringe. The flask was heated to 120° C. andstirred overnight. The flask was cooled to room temperature and dilutedwith water. The aqueous layer was extracted with DCM. The organic layerwas dried with Na₂SO₄, filtered and concentrated. The crude product wasadded to a silica gel column and was eluted with ethyl acetate/hexane 0%to 100% to give methyl 3-morpholinofuran-2-carboxylate (257 mg, 57%yield) as a white solid. ESI MS m/z=212.1 [M+H]⁺.

Example 348 Step b

Example 348 was prepared using a procedure similar to that used toprepare Example 152 where methyl 3-morpholinofuran-2-carboxylate wasused in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI MSm/z=471.2 [M+H]⁺.

Example 349

Example 349 Step a

In a round-bottomed flask fit with condenser,1-phenyl-1H-pyrazole-5-carboxylic acid (1 g, 5.31 mmol) was dissolved inmethanol (13 mL). The flask was cooled to 0° C. and SOCl₂ (1.2 mL, 16.47mmol) was added dropwise. The flask was warmed to 60° C. and stirredovernight. The flask was cooled to room temperature and quenched withwater. The aqueous layer was basified with saturated NaHCO₃ andextracted with EtOAc. The organic layer was dried with Na₂SO₄, filteredand concentrated. Methyl 1-phenyl-1H-pyrazole-5-carboxylate (0.93 g, 87%yield) was isolated as a white solid. ESI MS m/z=203.1 [M+H]⁺.

Example 349 Step b

Example 349 was prepared using a procedure similar to that used toprepare Example 152 where methyl 1-phenyl-1H-pyrazole-5-carboxylate wasused in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI MSm z=462.2 [M+H]⁺.

Example 350

Example 350 Step a

In a round-bottomed flask fit with condenser,1-phenyl-1H-pyrazole-3-carboxylic acid (0.25 g, 1.33 mmol) was dissolvedin methanol (6 mL). The flask was cooled to 0° C. andtrimethylsilyldiazomethane (2.7 mL, 5.32 mmol, 2M) was added dropwise tothe flask. The flask was warmed to room temperature and stirred for twohours. The reaction mixture was concentrated and taken up in EtOAc andwater. The aqueous layer was extracted with EtOAc (3×). The organiclayer was dried with NaSO₄, filtered and concentrated. The crude productwas added to a silica gel column and was eluted with ethylacetate/hexane 0% to 50% to afford methyl1-phenyl-1H-pyrazole-3-carboxylate (136 mg, 51% yield) as a white solid.ESI MS m/z=203.1 [M+H]⁺.

Example 350 Step b

Example 350 was prepared using a procedure similar to that used toprepare Example 152 where methyl 1-phenyl-1H-pyrazole-3-carboxylate wasused in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI MSm/z=462.2 [M+H]⁺.

Example 351

Example 351 was prepared using a procedure similar to that used toprepare Example 152 where ethyl 2-morpholinothiazole-4-carboxylate wasused in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI MSm/z=488.2 [M+H]⁺.

Example 352

Example 352 was prepared using a procedure similar to that used toprepare Example 20 where 2-iodobenzoic acid was used in place of5-chlorofuran-2-carboxylic acid. ESI MS m/z=522.0 [M+H]⁺.

Example 353

Example 353 was prepared using a procedure similar to that used toprepare Example 345 where3-((5-(2-iodophenyl)-1,3,4-oxadiazol-2-yl)amino)-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-onewas used in place of methyl 5-bromo-2-methylthiazole-4-carboxylate. ESIMS m/z=478.2 [M+H]⁺.

Example 354

Example 354 was prepared using a procedure similar to that used toprepare Example 346 where3-((5-(2-(3,6-dihydro-2H-pyran-4-yl)phenyl)-1,3,4-oxadiazol-2-yl)amino)-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-onewas used in place of(S)-3-((5-(5-(3,6-dihydro-2H-pyran-4-yl)-2-methylthiazol-4-yl)-1,3,4-oxadiazol-2-yl)amino)-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one.ESI MS m/z=480.3 [M+H]⁺.

Example 355

Example 355 Step a

A solution of 2-amino-3-fluorobenzonitrile (25 g, 0.18 mol) in THF (400mL) was added dropwise PhMgBr (120 mL, 3 M) at 0° C. under N₂ over 30min. The reaction mixture was stirred for 2 hrs at rt. Then HCl/H₂O (400mL, 6 M) was added and the reaction mixture was stirred O/N at roomtemperature. LCMS showed that the reaction was complete. The organiclayer was removed, the residue phase was extracted with EA (×3). Thecombined organic layers was washed with brine, dried over Na₂SO₄ andpurified by silica gel chromatography (PE/EA=1/0-10/1) to give thedesired compound as a yellow solid (31.5 g, 78%). ESI-MS m z: 216.0[M+H]⁺.

Example 355 Step b

3-amino-9-fluoro-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one wasprepared using a procedure similar to that used to prepare(Z)-3-amino-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one in Example 1where (2-amino-3-fluorophenyl)(phenyl)methanone was used in place of2-benzoylaniline. ESI-MS m z: 270.1 [M+H]⁺.

Example 355 Step c

Example 355 was prepared using a procedure similar to that used toprepare Example 21 where3-amino-9-fluoro-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one and2-morpholinobenzohydrazide were used in place of(Z)-3-amino-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one andtetrahydro-2H-pyran-4-carbohydrazide, respectively. ESI-MS m/z: 499.4[M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 2.83-2.93 (m, 4H), 3.69 (dd, J=5.4,3.4 Hz, 4H), 5.15-5.24 (m, 1H), 7.11-7.18 (m, 3H), 7.25-7.32 (m, 1H),7.40-7.72 (m, 8H), 9.02 (d, J=7.9 Hz, 1H), 10.92 (t, J=13.9 Hz, 1H).

Example 355 (300 mg, 0.60 mmol) was purified by Chiral Separation togive the product 355a as a light yellow solid (102 mg, 33%) and 355b asan a light yellow solid (103 mg, 35%).

Example 355a

ESI-MS m/z: 499.0 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 2.88 (dd, J=5.6,3.5 Hz, 4H), 3.70 (dd, J=5.6, 3.5 Hz, 4H), 5.25 (d, J=8.7 Hz, 1H),7.07-7.24 (m, 3H), 7.30-7.37 (m, 1H), 7.41-7.72 (m, 8H), 9.13 (d, J=8.7Hz, 1H), 10.96 (s, 1H).

Example 355b

ESI-MS m/z: 499.1 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 2.83-2.93 (m, 4H),3.65-3.75 (m, 4H), 5.25 (d, J=8.6 Hz, 1H), 7.07-7.24 (m, 3H), 7.30-7.37(m, 1H), 7.41-7.72 (m, 8H), 9.13 (d, J=8.7 Hz, 1H), 10.96 (s, 1H).

Example 356

Example 355 was prepared using a procedure similar to that used toprepare Example 355 where 4-morpholinobenzohydrazide was used in placeof 2-morpholinobenzohydrazide. ESI-MS m/z: 499.4 [M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 3.23 (t, J=4.9 Hz, 4H), 3.74 (dd, J=6.1, 3.6 Hz, 4H),5.21 (d, J=8.5 Hz, 1H), 7.01-7.13 (m, 2H), 7.18 (dd, J=8.0, 1.3 Hz, 1H),7.32 (td, J=8.0, 4.9 Hz, 1H), 7.40-7.72 (m, 8H), 8.96 (d, J=8.6 Hz, 1H),10.93 (s, 1H).

Examples 357 and 358

Examples 357 and 358 were prepared using a procedure similar to thatused to prepare Example 355 where 2-morpholinonicotinohydrazide was usedin place of 2-morpholinobenzohydrazide, followed by chiral separation.

Example 357: ESI-MS m/z: 500.2 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 3.15(d, J=5.0 Hz, 4H), 3.68 (d, J=4.9 Hz, 4H), 5.25 (d, J=8.5 Hz, 1H),6.99-7.09 (m, 1H), 7.18 (d, J=8.0 Hz, 1H), 7.26-7.40 (m, 1H), 7.48-7.65(m, 6H), 7.97 (d, J=7.5 Hz, 1H), 8.35 (d, J=4.7 Hz, 1H), 9.19 (d, J=8.5Hz, 1H), 10.96 (s, 1H). Example 358: ESI-MS m/z: 500.2 [M+H]⁺. ¹H NMR(300 MHz, DMSO-d₆) δ 3.14 (s, 4H), 3.69 (d, J=6.5 Hz, 4H), 5.25 (d,J=8.4 Hz, 1H), 6.98-7.09 (m, 1H), 7.18 (d, J=8.0 Hz, 1H), 7.33 (q, J=7.2Hz, 1H), 7.45-7.65 (m, 6H), 7.97 (d, J=7.5 Hz, 1H), 8.35 (d, J=5.3 Hz,1H), 9.20 (d, J=8.5 Hz, 1H), 10.96 (s, 1H).

Examples 359 and 360

Examples 359 and 360 were prepared using a procedure similar to thatused to prepare Example 355 where3-morpholino-5-(trifluoromethyl)picolinohydrazide was used in place of2-morpholinobenzohydrazide, followed by chiral separation.

Example 359: ESI-MS m/z: 568.4 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 3.07(dd, J=5.7, 3.2 Hz, 4H), 3.61-3.77 (m, 4H), 5.30 (d, J=8.2 Hz, 1H), 7.19(d, J=7.9 Hz, 1H), 7.30-7.37 (m, 1H), 7.41-7.75 (m, 6H), 7.89 (s, 1H),8.69 (s, 1H), 9.43 (d, J=8.4 Hz, 1H), 10.90 (s, 1H).

Example 360: ESI-MS m/z: 568.4 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ3.02-3.12 (m, 4H), 3.72 (dd, J=5.9, 3.2 Hz, 4H), 5.29 (d, J=8.3 Hz, 1H),7.19 (dd, J=7.9, 1.4 Hz, 1H), 7.30-7.37 (m, 1H), 7.41-7.70 (m, 6H), 7.89(s, 1H), 8.69 (s, 1H), 9.43 (d, J=8.5 Hz, 1H), 10.92 (s, 1H).

Example 361

Example 361 was prepared using a procedure similar to that used toprepare Example 325, except that(S)-3-amino-9-fluoro-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-onewas used in place of(S)-3-amino-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one (A). The(S)-3-amino-9-fluoro-5-phenyl-1,3-dihydro-21H-benzo[e][1,4]diazepin-2-onewas prepared in a similar way as(S)-3-amino-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one (A).ESI-MS m/z: 525.3 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 3.03 (s, 4H),3.72-3.80 (m, 4H), 5.23-5.31 (m, 1H), 7.18-7.20 (m, 1H), 7.30-7.37 (m,1H), 7.45-7.66 (m, 6H), 8.13-8.14 (m, 1H), 8.73 (m, 1H), 9.41-9.49 (m,1H), 10.96 (s, 1H).

Example 362

Example 355 was prepared using a procedure similar to that used toprepare Example 355 where 2-amino-3-chlorobenzonitrile were used inplace of 2-amino-3-fluorobenzonitrile. ESI-MS m/z: 499.4 [M+H]⁺. ¹H NMR(300 MHz, DMSO-d₆) δ 2.83-2.93 (m, 4H), 3.62-3.77 (m, 4H), 5.18 (d,J=8.5 Hz, 1H), 7.07-7.22 (m, 2H), 7.33 (d, J=4.6 Hz, 2H), 7.41-7.61 (m,6H), 7.67 (dd, J=7.7, 1.6 Hz, 1H), 7.85 (q, J=4.2 Hz, 1H), 9.13 (d,J=8.7 Hz, 1H), 10.64 (s, 1H).

Example 363

Example 363 was prepared using a procedure similar to that used toprepare Example 86 where 4-fluorobenzoyl isothiocyanate was used inplace of benzoyl isothiocyanate. ESI-MS m z: 413.3 [M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 5.19 (d, J=8.8 Hz, 1H), 7.15-7.72 (m, 12H), 7.79-7.93(m, 2H), 10.97 (s, 1H), 12.26 (s, 1H).

Example 364

Example 364 Step a

A solution of the1-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)thioureafrom Example 90 step a (1.2 g, 3.9 mol) and MeI (577 mg, 4.1 mmol) inMeOH (20 mL) was refluxed for 1 hour. It was concentrated to give 1.4 g(crude) of desired compound as orange solid, which was used directly inthe next step. ESI-MS m/z: 325.0 [M+H]⁺.

Example 364 Step b

A solution of the compound from step a (150 mg, 0.463 mmol),4-(1H-pyrazol-1-yl)benzohydrazide (103 mg, 0.51 mmol) in pyridine (5 mL)was refluxed for 1 hour in an oil bath. The crude product was purifiedby Prep-HPLC (MeCN/H₂O) to give the title compound as a white solid (27mg, 13%). ESI-MS m/z: 461.4 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 5.21 (d,J=8.8 Hz, 1H), 6.55 (m, 1H), 7.22-7.58 (m, 9H), 7.57-7.82 (m, 2H), 7.90(m, 4H), 8.51 (d, J=2.5 Hz, 1H), 10.97 (s, 1H), 12.40 (s, 1H).

Example 365

Example 365 was prepared using a procedure similar to that used toprepare Example 364 where 4-cyanobenzohydrazide was used in place of4-(1H-pyrazol-1-yl)benzohydrazide. ESI-MS m/z: 420.3 [M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 5.21 (d, J=8.6 Hz, 1H), 7.20-7.37 (m, 3H), 7.38-7.55 (m,5H), 7.66 (m, 2H), 7.84 (d, J=8.3 Hz, 2H), 7.93-8.08 (m, 2H), 10.97 (s,1H), 12.66 (s, 1H).

Example 366

Example 366 was prepared using a procedure similar to that used toprepare Example 364 where isonicotinohydrazide was used in place of4-(1H-pyrazol-1-yl)benzohydrazide. ESI-MS m/z: 396.3 [M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 5.23 (d, J=8.6 Hz, 1H), 7.20-7.54 (m, 8H), 7.57-7.84 (m,4H), 8.51-8.69 (m, 2H), 10.98 (d, J=11.8 Hz, 1H), 12.62 (s, 1H).

Example 367

Example 367 was prepared using a procedure similar to that used toprepare Example 364 where 2-morpholinobenzohydrazide was used in placeof 4-(1H-pyrazol-1-yl)benzohydrazide. ESI-MS m/z: 480.4 [M+H]⁺. ¹H NMR(300 MHz, DMSO-d₆) δ 2.77 (m, 4H), 3.62 (s, 4H), 5.21 (d, J=8.8 Hz, 1H),7.10 (s, 2H), 7.21-7.29 (m, 2H), 7.29-7.36 (m, 2H), 7.46 (m, 5H),7.59-7.68 (m, 2H), 10.89 (s, 1H), 12.80 (s, 1H).

Example 368

Example 368 was prepared using a procedure similar to that used toprepare Example 84 where 4-(2-azidoacetyl)benzonitrile was used in placeof 2-azido-1-phenylethanone. ESI-MS m/z: 410.1 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ5.20 (s, 1H), 7.25-7.28 (m, 1H), 7.33-7.35 (m, 2H), 7.43-7.49(m, 6H), 7.51-7.55 (m, 3H), 7.64-7.86 (m, 2H), 9.00 (s, 1H), 10.95 (s,1H).

Example 369

Example 369 was prepared using a procedure similar to that used toprepare Example 84 where 2-azido-1-(4-fluorophenyl)ethan-1-one was usedin place of 2-azido-1-phenylethanone. ESI-MS m/z: 413.1 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆) δ5.17-5.19 (d, J=8.0, 1H), 7.10-7.14 (m, 1H),7.19-7.26 (m, 3H), 7.27-7.36 (m, 3H), 7.44-7.49 (m, 2H), 7.51-7.57 (m,7H), 7.65-7.69 (m, 1H), 8.70-8.73 (m, 1H), 10.95 (s, 1H).

Example 370

Example 370 was prepared using a procedure similar to that used toprepare Example 84 where 2-azido-1-(4-bromophenyl)ethan-1-one was usedin place of 2-azido-1-phenylethanone. ESI-MS m/z: 475.0 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆) δ5.17-5.19 (d, J=8.0 Hz, 1H), 7.25-7.29 (m, 2H),7.33-7.35 (m, 2H), 7.44-7.49 (m, 7H), 7.51-7.59 (m, 2H), 7.61-7.68 (m,1H), 8.75-8.77 (d, J=8.0 Hz, 1H), 10.93 (s, 1H).

Example 371

Example 371 was prepared using a procedure similar to that used toprepare Example 95 where 2-chloro-5-phenylpyrimidine was used in placeof 3-chloro-6-phenylpyridazine. ESI-MS m/z: 406.3 [M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 5.56 (d, J=7.6 Hz, 1H), 7.30 (m, 2H), 7.47 (m, 10H),7.62-7.77 (m, 2H), 7.95 (s, 1H), 8.20 (d, J=7.7 Hz, 1H), 8.37 (s, 1H),10.95 (s, 1H).

Example 372

Example 372 was prepared using a procedure similar to that used toprepare Example 86 where cyclopropanecarbonyl isothiocyanate was used inplace of benzoyl isothiocyanate. ESI-MS m/z: 359.3 [M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 0.77 (d, J=35.3 Hz, 4H), 1.77 (m, 1H), 5.03 (d, J=9.0Hz, 1H), 7.19-7.37 (m, 3H), 7.39-7.55 (m, 5H), 7.63 (m, 1H), 8.19 (s,1H), 10.86 (s, 1H).

Example 373

Example 373 was prepared using a procedure similar to that used toprepare Example 95 where 2-chloro-5-(4-fluorophenyl)pyrazine was used inplace of 3-chloro-6-phenylpyridazine. ESI-MS m/z: 424.3 [M+H]⁺. ¹H NMR(300 MHz, DMSO-d₆) δ 5.52 (d, J=7.7 Hz, 1H), 7.27 (m, 3H), 7.33-7.41 (m,2H), 7.42-7.60 (m, 5H), 7.67 (m, 1H), 7.90-8.03 (m, 2H), 8.30-8.46 (m,2H), 8.48-8.58 (m, 1H), 10.76-11.18 (m, 1H).

Example 374

Example 374 was prepared using a procedure similar to that used toprepare Example 95 where 3-chloro-6-(4-fluorophenyl)pyridazine was usedin place of 3-chloro-6-phenylpyridazine. ESI-MS m/z: 424.3 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 5.64 (d, J=6.2 Hz, 1H), 7.23-7.40 (m, 5H),7.41-7.61 (m, 6H), 7.68 (m, 1H), 7.94-8.18 (m, 3H), 8.79 (s, 1H), 11.02(s, 1H).

Example 375

Example 375 was prepared using a procedure similar to that used toprepare Example 95 where 3-chloro-6-(pyridin-4-yl)pyridazine was used inplace of 3-chloro-6-phenylpyridazine. ESI-MS m/z: 407.3 [M+H]⁺. ¹H NMR(300 MHz, DMSO-d₆) δ 5.73 (d, J=7.5 Hz, 1H), 7.24-7.43 (m, 4H),7.43-7.62 (m, 5H), 7.69 (m, 1H), 7.93-8.02 (m, 2H), 8.06 (d, J=9.4 Hz,1H), 8.38 (d, J=7.6 Hz, 1H), 8.62-8.72 (m, 2H), 10.93 (s, 1H).

Example 376

Example 376 was prepared using a procedure similar to that used toprepare Example 95 where 3-chloro-6-(4-methoxyphenyl)pyridazine was usedin place of 3-chloro-6-phenylpyridazine. ESI-MS m/z: 436.4 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 3.79 (s, 3H), 5.68 (d, J=7.8 Hz, 1H), 6.96-7.07(m, 2H), 7.28 (m, 2H), 7.36 (m, 2H), 7.43-7.53 (m, 4H), 7.67 (m, 1H),7.83-7.95 (m, 3H), 8.03 (d, J=7.9 Hz, 1H), 8.44 (s, 1H), 10.92 (s, 1H).

Example 377

Example 377 was prepared using a procedure similar to that used toprepare Example 95 where 4-(6-chloropyridazin-3-yl)benzonitrile was usedin place of 3-chloro-6-phenylpyridazine. ESI-MS m/z: 431.4 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 5.74 (d, J=7.4 Hz, 1H), 7.27-7.43 (m, 4H),7.44-7.59 (m, 5H), 7.66-7.75 (m, 1H), 7.92-8.01 (m, 2H), 8.03-8.12 (m,1H), 8.16-8.26 (m, 2H), 8.37 (d, J=7.4 Hz, 1H), 10.96 (s, 1H).

Example 378

Example 378 was prepared using a procedure similar to that used toprepare Example 95 where 4-(2-(6-chloropyridazin-3-yl)phenyl)morpholinewas used in place of 3-chloro-6-phenylpyridazine. ESI-MS m/z: 491.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 2.66-2.84 (m, 4H), 3.49-3.66 (m,4H), 5.70 (m, 1H), 7.07-7.19 (m, 2H), 7.19-7.31 (m, 2H), 7.35 (m, 3H),7.43-7.57 (m, 6H), 7.67 (m, 1H), 7.96 (m, 1H), 8.08 (d, J=7.9 Hz, 1H),10.68 (s, 1H).

Example 379

Example 379 Step a

A solution of aniline (4.65 g, 50 mmol) in DCE (100 mL) was stirred for10 minutes at 0° C. Then BCl₃ (55 ml, 55 mmol, 1M in DCM) was addedslowly before it was stirred for 30 minutes at 0° C.2-fluorobenzonitrile (12 g, 100 mmol) and AlCl₃ (7.38 g, 55 mmol) wereadded and the mixture was heated to 80° C. overnight. Solid was filteredout and the filtrate was concentrated under vacuum, it was diluted withwater (100 mL) and extracted with EA (3×100 mL). The organic phase wasconcentrated under vacuum. The crude product was used directly in thenext step. ESI-MS m/z: 215.1 [M+H]⁺.

Example 379 Step b

A solution of the compound from step a (8.79 g, 41.8 mmol) in HCl (60mL) was stirred for 40 minutes at 0° C. The solution was heated up to80° C. for an hour. The crude product was purified by Flash (MeCN/H₂O)to give desired compound as a yellow solid (2.3 g, 27%). ESI-MS m/z:216.1 [M+H]⁺.

Example 379 Step c

A solution of (COCl)₂ (1.85 g, 14.2 mmol) was added dropwise to2-(1H-benzo[d][1,2,3]triazol-1-yl)-2-(benzyloxycarbonylamino)aceticacid, prepared in Example 1 step a, (3.6 g, 11 mmol) and DMF (0.5 mL) inTHF (100 mL) at 0° C. and stirred for 1 h, then(2-aminophenyl)(2-fluorophenyl)methanone (1.08 g, 5.0 mmol) and NMM(1.01 g, 10.0 mmol) was added to the mixture at 0° C. and stirred for 1h at rt. Filtered and NH₃.H₂O (7N) in MeOH (50 mL) was added and stirredfor 2 h, extracted with EA (100 mL×3), washed with aq. NaOH (1N, 200mL), dried (Na₂SO₄), concentrated and dissolved by HOAc (50 mL), thenNH₄OAc (4.37 g, 31.0 mmol) was added and stirred for 18 h at rt. Thesolvents were removed and it was adjusted PH to 9-10, washed with Et₂O(50 mL) to afford the desired compound as an off-white solid (940 mg,47%). ESI-MS m/z: 404.1 [M+H]⁺.

Example 379 Step d

The compound from step c (940 mg, 2.3 mmol) was dissolved in HBr/HOAc (3mL) and stirred for 30 min at 70° C. The reaction mixture was cooled at0° C. and Et₂O (30 mL) was added, filtered to afford the desiredcompound as a yellow solid (142 mg, 23%). ESI-MS m/z: 270.1 [M+H]⁺.

Example 379 Step e

A solution of the compound from step d (142 mg, 0.53 mmol), TEA (1 mL)and TCDI (140 mg, 0.79 mmol) in DMF (20 mL) and stirred for 1 h at 25°C. Then 4-fluorobenzohydrazide (120 mg, 0.78 mmol) and EDCI (764 mg, 4mmol) was added to the mixture and stirred for 2 h at 60° C. The mixturewas cooled to 0° C. and H₂O (60 mL) was added. Solid was collected andpurified by Prep-HPLC (MeCN/H₂O) to afford the title compound as a lightyellow solid (21 mg, 9%). ESI-MS m/z: 432.3 [M+H]⁺. ¹H NMR (300 MHz,DMSO-d₆) δ 5.17 (d, J=8.6 Hz, 1H), 7.15-7.48 (m, 7H), 7.50-7.71 (m, 3H),7.80-7.94 (m, 2H), 9.17 (d, J=8.6 Hz, 1H), 11.08 (s, 1H).

Example 380

Example 380 was prepared using a procedure similar to that used toprepare Example 379 where 3-fluorobenzonitrile was used in place of2-fluorobenzonitrile. ESI-MS m/z: 432.1 [M+H]⁺. ¹H NMR (300 MHz,DMSO-d₆) δ 5.18 (d, J=8.3 Hz, 1H), 7.22-7.48 (m, 8H), 7.49-7.58 (m, 1H),7.70 (t, J=7.4 Hz, 1H), 7.81-7.96 (m, 2H), 9.18 (d, J=8.4 Hz, 1H), 11.06(s, 1H).

Example 381

Example 381 was prepared using a procedure similar to that used toprepare Example 379 where isophthalonitrile was used in place of2-fluorobenzonitrile. ESI-MS m/z: 439.3 [M+H]⁺. ¹H NMR (300 MHz,DMSO-d₆) δ 5.18 (d, J=8.3 Hz, 1H), 7.22-7.48 (m, 8H), 7.49-7.58 (m, 1H),7.70 (t, J=7.4 Hz, 1H), 7.81-7.96 (m, 2H), 9.18 (d, J=8.4 Hz, 1H), 11.06(s, 1H).

Example 382

Example 382 was prepared using a procedure similar to that used toprepare Example 379 where 4-fluorobenzonitrile was used in place of2-fluorobenzonitrile. ESI-MS m/z: 432.3 [M+H]⁺. ¹H NMR (300 MHz,DMSO-d₆) δ 5.16 (d, J=8.5 Hz, 1H), 7.24-7.50 (m, 7H), 7.51-7.64 (m, 2H),7.70 (m, 1H), 7.82-7.95 (m, 2H), 9.16 (d, J=8.5 Hz, 1H), 11.02 (s, 1H).

Example 383

Example 383 Step a

A solution of methyl 2-aminothiophene-3-carboxylate (6.0 g, 38.4 mmol)was dissolved in DMA (40 mL), then 1-bromo-2-(2-bromoethoxy)ethane (26.5g, 115 mmol) and Cs₂CO₃ (37.5 g, 115.0 mmol) was added. The mixture wasstirred at 80° C. for 5 hours. It was diluted with H₂O, and extractedwith EA (×3) and washed with brine (×2). The organic layers was combinedand concentrated, then purified by reverse phase C18 columnchromatography (MeCN/H₂O) to give desired compound as brown liquid (8.0g). ESI MS m/z=227.9 [M+H]⁺.

Example 383 Step b

A solution of iodosobenzene diacetate (4.83 g, 15 mmol) was added to thecompound from step a (1.14 g, 5 mmol), TMSCF₃ (2.13 g, 15 mmol) and KF(870 mg) in DMSO (40 mL) was stirred for 0.5 hour at r.t. It wasquenched by H₂O (50 mL) and extracted with DCM (3×), dried Na₂SO₄,filtered to give crude methyl2-morpholino-5-(trifluoromethyl)thiophene-3-carboxylate as a brown oil.(5 g). ESI MS m/z=296.2 [M+H]⁺.

Example 383 Step c

Example 404 was prepared using a procedure similar to that used toprepare Example 152 where methyl2-morpholino-5-(trifluoromethyl)thiophene-3-carboxylate was used inplace of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI MSm/z=555.4 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 3.11-3.21 (m, 4H),3.67-3.77 (m, 4H), 5.12 (d, J=8.5 Hz, 1H), 7.20-7.38 (m, 3H), 7.38-7.58(m, 5H), 7.59-7.72 (m, 2H), 9.06 (d, J=8.6 Hz, 1H), 10.97 (s, 1H).

Example 384

Example 384 Step

A solution of methyl 2-morpholinothiophene-3-carboxylate, from 383 stepa, (5.0 g, 22 mmol), HBr (2 mL) and DMSO (2 mL) in EA (4 mL) was stirredat rt for 1 hour. The resulting solution was diluted with water andextracted with EA (×3). The organic phase was concentrated and purifiedby reverse phase C18 column chromatography (MeCN/H₂O) to give thedesired product as a brown solid (1.6 g, 24%). ESI MS m/z=306.2 [M+H]⁺.

Example 384 Step b

A solution of the compound from step a (488 mg, 1.6 mmol),cyclopropylboronic acid (276 mg, 3.2 mmol), Pd(OAc)₂ (72 mg, 0.32 mmol),Pcy₃.HBF₄ (118 mg, 0.32 mmol) and K₃PO₄ (680 mg, 3.2 mmol) in H₂O (2 mL)and toluene (10 mL) was stirred for one hour at 100° C. It wasconcentrated, and diluted with EA. The solid was filtered out. Thefiltrate was washed with brine (×2). The organic layers was combined andconcentrated and purified by reverse phase C18 column chromatography(MeCN/H₂O) to give methyl5-cyclopropyl-2-morpholinothiophene-3-carboxylate as brown oil 660 mg.ESI MS m/z=268.3 [M+H]⁺.

Example 384 Step c

Example 384 was prepared using a procedure similar to that used toprepare Example 152 where methyl5-cyclopropyl-2-morpholinothiophene-3-carboxylate was used in place ofethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI MS m/z=527.2 [M+H]⁺.¹H NMR (300 MHz, DMSO-d₆) δ 0.60-0.75 (m, 2H), 0.84-1.02 (m, 2H),2.01-2.16 (ddt, J=13.3, 8.5, 4.8 Hz, 1H), 2.93-3.02 (m, 4H), 3.65-3.74(m, 4H), 5.08-5.18 (d, J=8.6 Hz, 1H), 6.86-6.93 (d, J=0.9 Hz, 1H),7.23-7.40 (m, 3H), 7.41-7.60 (m, 5H), 7.62-7.74 (ddd, J=8.5, 7.0, 1.8Hz, 1H), 8.92-9.01 (d, J=8.6 Hz, 1H), 10.95-11.02 (s, 1H).

Example 385

Example 385 step a:

A solution of ethyl 2-bromo-5-morpholinothiazole-4-carboxylate (10.0 g,42.6 mmol) and morpholine (4.076 g, 46.86 mmol) was dissolved in MeCN(100 mL), and then DBU (9.712 g, 63.9 mmol) was added. The mixture wasstirred at 80° C. for 1 hour. It was concentrated, and purified bysilica gel column with PE:EA=1:1 to give the target compound as a yellowgreen solid (6.17 g, 60%). ESI MS m/z=243.2 [M+H]⁺.

Example 385 Step b

A solution of the compound from step a (6.17 g, 25.51 mmol) and NBS (4.9g, 27.55 mmol) was dissolved in MeCN (100 mL), the mixture was stirredat RT for 1 hour. It was concentrated, and purified by silica gelchromatography with PE:EA=3:1 to give ethyl2-bromo-5-morpholinothiazole-4-carboxylate as a light yellow solid (7.53g, 92%). ESI MS m/z=320.9 [M+H]⁺.

Example 385 Step c

To a stirred solution of the ethyl2-bromo-5-morpholinothiazole-4-carboxylate (300 mg, 0.97 mmol) and ZnEt₂(229 mg, 1.87 mmol) in THF (10 mL) was added Pd(PPh₃)₄ (30 mg, 0.010mmol) under the nitrogen. The mixture was refluxed overnight and thenconcentrated. The reaction mixture was poured into saturated ice waterextracted with EA (3*100 ml). The organic layer was dried over Na₂SO₄.The residue was purified by flash chromatography (MeCN/H₂O) to giveethyl 2-ethyl-5-morpholinothiazole-4-carboxylate as a yellow solid (320mg). ESI MS m/z=271.2 [M+H]⁺.

Example 385 Step d

Example 385 was prepared using a procedure similar to that used toprepare Example 152 where ethyl2-ethyl-5-morpholinothiazole-4-carboxylate was used in place of ethyl2-morpholino-4-(trifluoromethyl)benzoate. ESI MS m/z=548.2 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ1.30 (3H, t), 2.95 (2H, t), 3.07 (4H, m), 3.72(4H, dd), 5.15 (1H, d), 7.34 (3H, m), 7.52 (5H, m), 7.68 (1H, m), 9.07(1H, d), 10.96 (1H, s).

Example 386

Example 387

Example 387 Step a

Cyclobutylzinc(II) bromide (7.6 mL, 3.8 mmol) was dropwised to asolution of ethyl 2-bromo-5-morpholinothiazole-4-carboxylate, preparedin Example 385, (1 g, 3.1 mmol) and Pd(PPh₃)₄ (361 mg, 0.031 mmol) inTHF (10 mL) at 0° C. under N₂. The mixture was stirred for 16 hours atreflux. The solution was quenched with water, concentrated, extractedwith EA (×3). The organic layers were combined, dried, concentrated. Thecrude product was purified by silica gel chromatography (PE-EA) to giveethyl 2-cyclobutyl-5-morpholinothiazole-4-carboxylate as yellow oil (740mg, 81%). ESI MS m/z=297.3 [M+H]⁺.

Example 387 Step b

Example 387 was prepared using a procedure similar to that used toprepare Example 152 where ethyl2-cyclobutyl-5-morpholinothiazole-4-carboxylate was used in place ofethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI MS m/z=542.4 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 1.89 (m, 1H), 1.97-2.07 (m, 1H), 2.20-2.31(m, 2H), 2.38 (m, 2H), 3.07 (m, 4H), 3.66-3.75 (m, 4H), 3.75-3.83 (m,1H), 5.15 (d, J=8.6 Hz, 1H), 7.25-7.40 (m, 3H), 7.51 (m, 5H), 7.68 (m,1H), 9.07 (d, J=8.7 Hz, 1H), 10.88-11.03 (m, 1H).

Example 388

Example 388 was prepared using a procedure similar to that used toprepare Example 338 where 3-pyridylboronic acid was used in place ofcyclopropylboronic acid. ESI MS m/z=565.3 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 3.19-3.21 (m, 4H), 3.74-3.76 (m, 4H), 5.15-5.17 (d, J=8.0,1H), 7.27-7.37 (m, 5H), 7.45-7.57 (m, 6H), 7.66-7.69 (m, 1H), 8.21-8.24(m, 1H), 8.65-8.67 (m, 1H), 9.06-9.77 (m, 1H), 9.18-9.20 (m, 1H), 10.98(s, 1H).

Example 389

Example 389 Step a

A solution of ethyl 2-bromo-5-morpholinothiazole-4-carboxylate, preparedin Example 385, (1.0 g, 3.10 mmol), (5-fluoropyridin-2-yl) zinc (II)bromide (1488 mg, 6.20 mmol), Pd(PPh₃)₄ (340 mg, 0.31 mmol) in THF (25mL) was stirred at 65° C. for 5 hrs. Then H₂O (20 mL) was added to themixture and extracted with EA (×3). The organic layer was dried andpurified by reverse phase C18 column chromatography to give ethyl2-(5-fluoropyridin-2-yl)-5-morpholinothiazole-4-carboxylate as yellowsolid (110 mg, 11%).

Example 389 Step b

Example 389 was prepared using a procedure similar to that used toprepare Example 152 where ethyl2-(5-fluoropyridin-2-yl)-5-morpholinothiazole-4-carboxylate was used inplace of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI MSm/z=583.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 3.32-3.34 (m, 4H),3.74-3.75 (m, 4H), 5.16-5.18 (d, J=8.0, 1H), 7.27-7.29 (m, 1H),7.31-7.37 (m, 2H), 7.46-7.54 (m, 5H), 7.67-7.69 (m, 1H), 7.93-7.94 (m,1H), 8.07-8.11 (m, 1H), 8.65-8.66 (m, 1H), 9.17-9.18 (d, J=8.0, 1H),10.99 (s, 1H).

Example 390

Example 390 Step a

A solution of ethyl 2-bromo-5-morpholinothiazole-4-carboxylate, preparedin Example 385, (700 mg, 2.18 mmol),6-(trifluoromethyl)pyridin-3-ylboronic acid (460 mg, 2.40 mmol),Pd(dppf)Cl₂ (320 mg, 0.43 mmol) and Cs₂CO₃ (1.42 g, 4.37 mmol) wasstirred for 2 hrs at 90° C. in DMF (30 mL). It was purified by silicagel chromatography (PE:EA=5:1) to give ethyl5-morpholino-2-(6-(trifluoromethyl)pyridin-3-yl)thiazole-4-carboxylateas a yellow solid (460 mg, 54%). ESI MS m/z=388.2 [M+H]⁺.

Example 390 Step b

Example 390 was prepared using a procedure similar to that used toprepare Example 152 where ethyl5-morpholino-2-(6-(trifluoromethyl)pyridin-3-yl)thiazole-4-carboxylatewas used in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESIMS m z=633.4 [M+H]⁺. 1H NMR (300 MHz, DMSO-d₆) δ 3.26 (d, J=4.6 Hz, 4H),3.77 (t, J=4.3 Hz, 4H), 5.18 (d, J=8.5 Hz, 1H), 7.34 (m, J=18.2, 7.8 Hz,3H), 7.43-7.58 (m, 5H), 7.63-7.75 (m, 1H), 8.06 (d, J=8.3 Hz, 1H),8.45-8.53 (m, 1H), 9.19-9.27 (m, 2H), 10.99 (s, 1H).

Example 391

Example 392

Example 393

Examples 394 and 395

Examples 394 and 395 step a:

To a vial, add ethyl 5-bromo-2-(trifluoromethyl)thiazole-4-carboxylate(516 mg, 1.70 mmol), K₂CO₃ (352 mg, 2.55 mmol) and Pd(Ph₃P)₄ (392 mg,0.34 mmol). Evacuate and refill with N₂ and seal. Add toluene (8 mL),ethanol (8 mL) and water (4 mL) via syringe. Add(E)-2-(3-methoxyprop-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(0.432 mL, 2.036 mmol) via syringe. Heat vial to 80° C. and stirovernight. Dilute with water and extract with EtOAc (3×). Dry, filterand concentrate the organic layer. The crude product was added to asilica gel column and was eluted with ethyl acetate/hexane 0% to 50% togive ethyl(E)-5-(3-methoxyprop-1-en-1-yl)-2-(trifluoromethyl)thiazole-4-carboxylate(264 mg, 53% yield) as an oil.

Examples 394 and 395 Step b

To a oven dried vial, add ethyl(E)-4-(3-methoxyprop-1-en-1-yl)-2-(trifluoromethyl)thiazole-5-carboxylate(264 mg, 0.894 mmol) and DCM (12.8 mL). Cool to −10° C. Diethylzinc (4.5mL, 4.47 mmol) and diiodomethane (0.721 mL, 8.94 mmol), sequentially.Allow reaction mixture to warm to room temperature and stir for 2 days.Add diethylzinc (4.5 mL, 4.47 mmol) and diiodomethane (0.72 mL, 8.94mmol) at 0° C. Allow reaction mixture to warm to room temperature andstir for 3 days. After −5 days, the reaction mixture was quenched with10% HCl aq. and extracted with DCM (3×). Dry, filter and concentrate theorganic layer. The crude product was added to a silica gel column andwas eluted with ethyl acetate/hexane 0% to 50% to give ethyl4-(2-(methoxymethyl)cyclopropyl)-2-(trifluoromethyl)thiazole-5-carboxylate(51 mg, 18% yield) as an oil.

Examples 394 and 395 Step c

Examples 394 and 395 was prepared using a procedure similar to that usedto prepare Example 21 where ethyl4-(2-(methoxymethyl)cyclopropyl)-2-(trifluoromethyl)thiazole-5-carboxylatewas converted to it's corresponding hydrazide, similar to that describedin Example 152 step b, and was used in place oftetrahydro-2H-pyran-4-carbohydrazide. The racemic mixture was purifiedby chiral separation to give the desired compound as a mixture of transisomers with respect to the cyclopropane. (Column=YMC CHIRALCellulose-SB, 250*20 mm (5 uM); Mobile Phase=50% EtOH/50% hexanes; Flowrate=20 mL/min). ESI MS m/z=555.1 [M+H]⁺.

Example 396

Example 397

Example 398

Example 399

Example 399 Step a

A solution of ethyl 2-bromo-5-morpholinothiazole-4-carboxylate, preparedin Example 385, (1.0 g, 3.13 mmol), 1-methyl-1H-pyrazol-4-ylboronic acid(976 mg, 4.69 mmol), Cs₂CO₃ (863 mg, 6.25 mmol) and Pd(dppf)Cl₂ (511 mg,0.63 mmol) was dissolved in DMF (20 mL), then the mixture was stirred at90° C. overnight. It was concentrated, and purified by silica gelchromatography with PE:EA=1:1 to obtain ethyl2-(1-methyl-1H-pyrazol-4-yl)-5-morpholinothiazole-4-carboxylate as alight yellow solid (211 mg, 21%). ESI MS m/z=323.3 [M+H]⁺.

Example 399 Step b

Example 399 was prepared using a procedure similar to that used toprepare Example 152 where ethyl2-(1-methyl-1H-pyrazol-4-yl)-5-morpholinothiazole-4-carboxylate was usedin place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI MSm/z=568.5 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ3.17-3.02 (m, 4H),3.77-3.67 (m, 4H), 3.91 (s, 3H), 5.16 (d, 1H), 7.40-7.23 (m, 3H),7.59-7.40 (m, 5H), 7.69 (m, 1H), 7.87 (d, 1H), 8.29 (s, 1H), 9.13 (d,1H), 10.98 (s, 1H).

Example 400

Example 400 was prepared using a procedure similar to that used toprepare Example 21 where ethyl2-bromo-5-morpholinothiazole-4-carboxylate was converted to thecorresponding hydrazide, similar to that described in Example 152 stepb, and used in place of tetrahydro-2H-pyran-4-carbohydrazide. ESI MSm/z=568.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 3.13 (m, 4H), 3.71 (d,4H), 5.15 (d, 1H), 7.28 (m, 1H), 7.41-7.32 (m, 2H), 7.59-7.42 (m, 5H),7.68 (m, 1H), 9.16 (d, 1H), 10.97 (s, 1H).

Example 401

Example 401 Step a

NaH (360 mg, 0.015 mol) was added to the solution of ethyl3-amino-1H-pyrazole-4-carboxylate (2 g, 0.013 mol) in MeCN (30 mL) at 0°C. The mixture was stirred for 20 minutes at 0° C. Bromoethane (1.67 g,0.015 mol) was added and the mixture was stirred overnight. The solutionwas quenched with water, concentrated. The crude product was purifiedvia silica gel chromatography (DCM-MeOH) to give the mixture as yellowoil (1.25 g, 53%). ESI MS m/z=184.3 [M+H]⁺.

Example 401 Step b

A solution of the mixture from step 1 (1.25 g, 6.8 mmol),1-bromo-2-(2-bromoethoxy)ethane (3.1 g, 13.6 mmol), Cs₂CO₃ (4.44 g, 13.6mmol) in DMA (20 mL) was stirred overnight at 100° C. The mixture wasdiluted with water, extracted with EA (×3). The organic layers werecombined and washed with brine (×2), dried and concentrated. The residuewas purified by reverse phase C18 column chromatography (MeCN/H₂O) togive ethyl 1-ethyl-3-morpholino-1H-pyrazole-4-carboxylate as white solid(580 mg, 34%). ESI MS m/z=254.3 [M+H]⁺.

Example 401 Step c

Example 401 was prepared using a procedure similar to that used toprepare Example 152 where ethyl1-ethyl-3-morpholino-1H-pyrazole-4-carboxylate was used in place ofethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI MS m/z=499.4 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 1.36 (m, 3H), 3.17 (d, J=5.3 Hz, 4H),3.61-3.74 (m, 4H), 4.07 (m, 2H), 5.07-5.14 (m, 1H), 7.32 (m, 3H), 7.50(m, 5H), 7.68 (m, 1H), 8.09 (d, J=2.3 Hz, 1H), 8.91 (m, 1H), 10.98 (s,1H).

Example 402

Example 402 was prepared using a procedure similar to that used toprepare Example 401 where 1-bromo-2-methoxyethane was used in place ofbromoethane. ESI MS m/z=529.5 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 3.17(m, 4H), 3.25 (s, 3H), 3.67 (m, 6H), 4.20 (m, 2H), 5.10 (d, J=8.7 Hz,1H), 7.25-7.39 (m, 3H), 7.42-7.58 (m, 5H), 7.68 (m, 1H), 8.04 (s, 1H),8.91 (d, J=8.7 Hz, 1H), 10.96 (s, 1H).

Example 403

Example 403 Step a

A solution of 3-amino-1-isopropyl-1H-pyrazole-4-carboxylic acid (1 g, 6mmol) and H₂SO₄ (2 mL) in EtOH (5 mL) was refluxed for 5 hours. Thesolution was concentrated, adjusted pH=8 with saturated aqueous Na₂CO₃,extracted with EA (×3). The organic layers were combined, dried,concentrated to give desired 1.09 g (crude) as orange oil, that was useddirectly in the next step. ESI MS m/z=198.3 [M+H]⁺.

Example 403 Step b

A solution of the compound from step a (1.09 g, 5.5 mmol),1-bromo-2-(2-bromoethoxy)ethane (2.5 g, 11 mmol) and Cs₂CO₃ (3.6 g, 11mmol) in DMA (10 mL) was stirred overnight at 100° C. The solution wasdiluted with water, extracted with EA (×3), washed with brine (×2). Theorganic layer was dried, concentrated. The residue was purified viasilica gel chromatography (PE-EA) to give ethyl1-isopropyl-3-morpholino-1H-pyrazole-4-carboxylate as orange oil (1 g,67%). ESI MS m/z=268.4 [M+H]⁺.

Example 403 Step c

Example 403 was prepared using a procedure similar to that used toprepare Example 152 where ethyl1-isopropyl-3-morpholino-1H-pyrazole-4-carboxylate was used in place ofethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI MS m/z=513.4 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 1.41 (d, J=6.6 Hz, 6H), 3.10-3.19 (m, 4H),3.67 (m, 4H), 4.43 (m, 1H), 5.10 (d, J=8.7 Hz, 1H), 7.25-7.37 (m, 3H),7.43-7.56 (m, 5H), 7.67 (m, 1H), 8.07 (s, 1H), 8.87 (d, J=8.7 Hz, 1H),10.96 (s, 1H).

Example 404

Example 404 Step a

A solution of the ethyl 3-aminofuro [2, 3-b] pyridine-2-carboxylate (500mg, 2.42 mmol) in DMF (10 mL) was added NaH (387 mg, 9.68 mmol). It wasstirred at rt for 10 mins and then the 1-bromo-2-(2-bromoethoxy)ethane(1.67 g, 7.28 mmol) was added. The solution was stirred at rt for 2hours. Then H₂O (20 mL) was added to the mixture and extracted with EA(×3). The organic layer was dried and purified by reverse phase C18column chromatography to give ethyl3-morpholinofuro[2,3-b]pyridine-2-carboxylate as yellow solid (310 mg,46%). ESI MS m/z=276.9 [M+H]⁺.

Example 404 Step b

Example 404 was prepared using a procedure similar to that used toprepare Example 152 where ethyl3-morpholinofuro[2,3-b]pyridine-2-carboxylate was used in place of ethyl2-morpholino-4-(trifluoromethyl)benzoate. ESI MS m/z=522.2 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 3.36-3.39 (m, 4H), 3.73-3.76 (m, 4H), 5.18-5.20(d, J=8.0, 1H), 7.27-7.31 (m, 1H), 7.36-7.38 (m, 2H), 7.40-7.43 (m, 1H),7.45-7.49 (m, 2H), 7.52-7.56 (m, 3H), 7.67-7.71 (m, 1H), 8.42-8.46 (m,2H), 9.39-9.41 (d, J=8.0, 1H), 11.02 (s, 1H).

Example 405

Example 405 Step a

A solution of ethyl 2-bromo-5-morpholinothiazole-4-carboxylate, preparedin Example 385, (700 mg, 2.19 mmol), cyclohexenylboronic acid (303 mg,2.41 mmol), K₂CO₃ (604 mg, 4.38 mmol) and Pd(dppf)Cl₂ (160 mg, 0.219mmol) was dissolved in DMF (5 mL), then the mixture was stirred at 100°C. overnight. It was concentrated, and purified by silica gelchromatography with PE:EA=5:1 to obtain a yellow oil (571 mg, 81%). ESIMS m/z=322.6 [M+H]⁺.

Example 405 Step b

A solution of the compound from step a (700 mg, 2.19 mmol),cyclohexenylboronic acid (303 mg, 2.41 mmol), K₂CO₃ (604 mg, 4.38 mmol)and Pd(dppf)Cl₂ (160 mg, 0.22 mmol) was dissolved in DMF (5 mL), thenthe mixture was stirred at 100° C. overnight. It was concentrated, andpurified by silica gel column with PE:EA=5:1 to obtain ethyl2-cyclohexyl-5-morpholinothiazole-4-carboxylate as a yellow oil (571 mg,81%). ESI MS m/z=324.6 [M+H]⁺.

Example 405 Step c

Example 405 was prepared using a procedure similar to that used toprepare Example 152 where ethyl2-cyclohexyl-5-morpholinothiazole-4-carboxylate was used in place ofethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI MS m/z=570.5 [M+H]⁺.¹H NMR (300 MHz, DMSO-d₆) δ 1.55-1.16 (m, 5H), 1.90-1.63 (m, 3H), 2.04(d, 2H), 3.15-3.00 (m, 4H), 3.82-3.61 (m, 4H), 5.15 (d, 1H), 7.43-7.23(m, 3H), 7.62-7.43 (m, 5H), 7.68 (m, 1H), 9.08 (d, 1H), 10.97 (s, 1H).

Example 406

Example 406 Step a

A solution of the compound from step a (2.0 g, 6.25 mmol),ethynyltrimethylsilane (1420 mg, 12.50 mmol), Pd(PPh₃)Cl₂ (439 mg, 0.62mmol), PPh₃ (3.28 g, 12.50 mmol) and TEA (5 mL) in THF (50 mL) wasstirred at rt for 20 mins. Then CuI (2.4 g, 12.50 mmol) was added to thesolution and stirred at 65° C. for 2 hours. Then H₂O (20 mL) was addedto the mixture and extracted with EA (×3). The organic layer was driedand purified by reverse phase C18 column chromatography to give desiredcompound as yellow oil (1.25 g, 59%). ESI MS m/z=339.0 [M+H]⁺.

Example 406 Step b

A solution of the compound from step a (1.25 g, 3.70 mmol), LiOH (444mg, 18.49 mmol) in H₂O (10 mL), THF (10 mL) was stirred at rt for 5hours and the solution was adjusted pH value to 10. It was purified byreverse phase C18 column chromatography to give the desired compound asyellow solid (580 mg, 66%). ESI MS m/z=238.9 [M+H]⁺.

Example 406 Step c

Example 406 was prepared using a procedure similar to that used toprepare Example 151 where 2-ethynyl-5-morpholinothiazole-4-carboxylicacid was used in place of 6-fluoro-2-morpholinonicotinic acid. ESI MSm/z=512.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 3.17-3.20 (m, 4H),3.71-3.73 (m, 4H), 4.91 (s, 1H), 5.14-5.16 (d, J=8.0, 1H), 7.26-7.28 (m,1H), 7.30-7.36 (m, 2H), 7.45-7.48 (m, 2H), 7.51-7.55 (m, 3H), 7.65-7.69(m, 1H), 9.17-9.19 (d, J=8.0, 1H), 10.97 (s, 1H).

Example 407

Example 407 Step a

To a stirring solution of ethyl2-bromo-5-morpholinothiazole-4-carboxylate, prepared in Example 385,(400 mg, 1.25 mmol) in toluene (10 mL) was addedtributyl(1-ethoxyvinyl)stannane (905 mg, 2.5 mmol) and Pd(PPh₃)₄ (40 mg,0.001 mmol) at rt under the nitrogen. The mixture was refluxed for 2.5hours at 110° C. under the nitrogen and then concentrated. The reactionmixture was poured into water and extracted with EA (3*100 ml). Theorganic was dried over Na₂SO₄. The residue was purified by silica gelchromatography (PE/EA=3/1) to give the desired compound as a white solid(300 mg, 77%). ESI MS m/z=313.2 [M+H]⁺.

Example 407 Step b

The solution of compound from step a (300 mg, 0.96 mmol) was added tothe HCl (5 mL) in the dioxane (8 ml) at r.t. The resulting solution wasstirred at rt for 5 hrs. The reaction mixture was poured into saturatedNaHCO₃ liquid and extracted with EA (3*100 mL). The organic layer wasdried over Na₂SO₄ and purified to give the desired compound product as awhite solid (150 mg, 54%). ESI MS m/z=285.4 [M+H]⁺.

Example 407 Step c

To a stirring solution of the BAST (2 mL, 1.04 mmol) in DCM (5 mL) wasadded compound from step b (150 mg, 0.52 mmol) at rt. The resultingsolution was stirred at rt for 3 days. During the period, additionalBAST (5 mL) was added. The reaction mixture was poured into ice waterand extracted with DCM (3*100 mL). The organic layer was dried overNa₂SO₄ and purified by silica gel chromatography (PE/EA=1/1) to giveethyl 2-(1,1-difluoroethyl)-5-morpholinothiazole-4-carboxylate as ayellow solid (160 mg, 100%). ESI MS m/z=307.1 [M+H]⁺.

Example 407 Step d

Example 407 was prepared using a procedure similar to that used toprepare Example 152 where ethyl2-(1,1-difluoroethyl)-5-morpholinothiazole-4-carboxylate was used inplace of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI MSm/z=552.2 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ1.24 (1H, s), 2.12 (3H, t),3.20 (4H, m), 3.74 (4H, m), 5.15 (1H, d), 7.32 (3H, m), 7.50 (5H, m),7.67 (1H, m), 9.20 (1H, d), 10.98 (1H, s).

Example 408

Example 408 Step a

A solution of 6-methoxyquinoline-4-carboxylic acid (500 mg, 2.46 mmol)and H₂SO₄ (2 mL) in EtOH (10 mL) was stirred at 80° C. for 2 hours. ThenH₂O (20 mL) was added to the mixture and extracted with EA (×3). Theorganic layer was washed with NaHCO₃, brine and dried over Na₂SO₄ togive ethyl 6-methoxyquinoline-4-carboxylate as yellow solid (450 mg,79%). ESI MS m/z=231.9 [M+H]⁺.

Example 408 Step b

Example 408 was prepared using a procedure similar to that used toprepare Example 152 where ethyl 6-methoxyquinoline-4-carboxylate wasused in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI MSm/z=477.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 3.91 (s, 3H), 5.26 (s,1H), 7.29-7.32 (m, 1H), 7.37-7.39 (m, 2H), 7.45-7.49 (m, 2H), 7.51-7.54(m, 4H), 7.68-7.72 (m, 1H), 7.85-7.86 (m, 1H), 8.04-8.06 (m, 1H),8.56-8.57 (m, 1H), 8.91-8.93 (m, 1H), 9.52 (m, 1H), 10.93-10.94 (s, 1H).

Example 409

Example 409 Step a

A solution of 6-bromoquinoline-4-carboxylic acid (500 mg, 2.0 mmol),EtOH (10 mL) and H₂SO₄ (2 mL) was stirred for 4 hours at 80° C. It wasdiluted with H₂O, and extracted with EA (×3) and washed with brine (×2).The organic layers was combined and concentrated to give a brown solidproduct (420 mg, 75%) that was used without further purification. ESI MSm/z=280.2 [M+H]⁺.

Example 409 Step b

A solution of from step a (767 mg, 2.75 mmol), potassiumtrifluoro(methoxymethyl)borate (1.25 g, 8.25 mmol), Pd(OAc)₂ (123 mg,0.55 mmol), RuPhos (513 mg, 1.1 mmol), and Cs₂CO₃ (2.68 g, 8.25 mmol)was dissolved in degassed CPME (4.0 mL) and H₂O (1.0 mL), then themixture was stirred at 100° C. overnight under N₂. It was concentrated,and purified by silica gel chromatography with PE:EA=5:1 to obtain ethyl6-(methoxymethyl)quinoline-4-carboxylate as an orange oil (206 mg, 30%).ESI MS m/z=245.5 [M+H]⁺.

Example 409 Step c

Example 409 was prepared using a procedure similar to that used toprepare Example 152 where ethyl 6-(methoxymethyl)quinoline-4-carboxylatewas used in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESIMS m/z=491.4 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 3.33 (s, 3H), 4.67 (s,2H), 5.28 (d, 1H), 7.28-7.44 (m, 2H), 7.44-7.60 (m, 6H), 7.71 (m, 1H),7.82-7.90 (m, 2H), 8.13 (d, 1H), 9.01-9.14 (m, 2H), 9.54 (d, 1H), 11.06(s, 1H).

Example 410

Example 410 was prepared using a procedure similar to that used toprepare Example 152 where ethyl5-methoxypyrazolo[1,5-a]pyridine-3-carboxylate was used in place ofethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI MS m/z=466.2 [M+H]⁺.¹H NMR (300 MHz, DMSO-d₆) δ 3.92 (s, 3H), 5.16 (d, J=8.7 Hz, 1H), 6.80(dd, J=7.6, 2.7 Hz, 1H), 7.29 (t, J=7.6 Hz, 1H), 7.33-7.40 (m, 3H),7.44-7.58 (m, 5H), 7.66-7.70 (m, 1H), 8.33 (s, 1H), 8.73 (d, J=7.6 Hz,1H), 8.94 (d, J=8.7 Hz, 1H), 11.01 (s, 1H).

Example 411

Example 411 Step a

A solution of methyl 4-bromopyrazolo[1,5-a]pyridine-3-carboxylate (500mg, 1.97 mmol), potassium trifluoro(2-methoxyethyl)borate (490 mg, 1.28mmol), RuPhos (734 mg, 1.58 mmol), Pd(OAc)₂ (177 mg, 0.79 mmol) andCs₂CO₃ (1.92 g, 5.91 mmol) in CPME (8 mL) and water (2 mL) was stirredfor 5 hours at 100° C. under N₂. The mixture was diluted with water,extracted with EA (×3), the organic layer was dried, concentrated. Thecrude product was purified via silica gel chromatography (PE-EA) to givedesired compound as yellow solid (140 mg, 30%). ESI MS m/z=235.3 [M+H]⁺.

Example 411 Step b

Example 411 was prepared using a procedure similar to that used toprepare Example 152 where methyl4-(2-methoxyethyl)pyrazolo[1,5-a]pyridine-3-carboxylate was used inplace of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI MSm/z=494.4 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 3.15 (s, 2H), 3.41 (m,2H), 3.47 (m, 2H), 5.16 (d, J=8.6 Hz, 1H), 7.06 (m, 1H), 7.26-7.34 (m,2H), 7.36 (m, 2H), 7.43-7.63 (m, 5H), 7.68 (m, 1H), 8.36 (s, 1H), 8.74(m, 1H), 8.94-9.06 (m, 1H), 10.99 (s, 1H).

Examples 412 and 413

Examples 412 and 413 Step a

Pd(dppf)Cl₂ (0.7 g, 2.15 mmol) was added to the ethyl3-chloro-5-(trifluoromethyl)picolinate (1.64 g, 6.47 mmol), Cs₂CO₃ (2.7g, 8.6 mmol) and (E)-3-methoxyprop-1-enylboronic acid (0.5 g, 4.3 mmol)in DMF (30 mL) at rt under N₂. The mixture was stirred for 2 hours at100° C. The solution was diluted with EA, washed by brine. The organicphase was dried over anhydrous Na₂SO₄ and concentrated. The crudeproduct was purified via silica gel chromatography (PE-EA) to givedesired compound as yellow solid (0.53 g, 43%). ESI MS m/z=290.0 [M+H]⁺.

Examples 412 and 413 Step b

A solution of the compound from step a (300 mg, 1.0 mmol) and NH₂NH₂.H₂O(2 mL) in EtOH (5 mL) was refluxed for 2 hours. The crude product waspurified by reverse phase C18 column chromatography (MeCN/H₂O) to give amixture of A and B as a yellow solid (˜20% of the olefin was reduced asA) (200 mg, 70%). A ESI MS m/z=276.3 [M+H]⁺. B ESI MS m/z=278.3 [M+H]⁺.

Examples 412 and 413 Step c

Examples 412 and 413 were prepared using a procedure similar to thatused to prepare Example 152 where(E)-3-(3-methoxyprop-1-en-1-yl)-5-(trifluoromethyl)picolinohydrazide and3-(3-methoxypropyl)-5-(trifluoromethyl)picolinohydrazide were used inplace of 2-morpholino-4-(trifluoromethyl)benzohydrazide. Example 418 ESIMS m/z=535.4 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 3.32 (s, 3H), 4.11 (m,2H), 5.22 (d, J=8.4 Hz, 1H), 6.75 (m, 1H), 7.27-7.33 (m, 1H), 7.36 (m,2H), 7.44-7.50 (m, 2H), 7.50-7.63 (m, 4H), 7.69 (m, 1H), 8.57 (d, J=2.1Hz, 1H), 8.95-9.10 (m, 1H), 9.50 (d, J=8.4 Hz, 1H), 11.01 (s, 1H).Example 419 ESI MS m/z=537.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ1.72-1.96 (m, 2H), 3.11-3.25 (m, 4H), 3.33 (s, 3H), 5.22 (d, J=7.9 Hz,1H), 7.25-7.32 (m, 1H), 7.33-7.41 (m, 2H), 7.43-7.50 (m, 2H), 7.50-7.60(m, 3H), 7.68 (m, 1H), 8.27 (d, J=2.1 Hz, 1H), 8.88-9.10 (m, 1H), 9.47(d, J=8.4 Hz, 1H), 10.99 (s, 1H).

Example 414

Examples 414 Step a

The compound 3-fluoro-5-(trifluoromethyl)picolinic acid (2.0 g, 9.56mmol) was dissolved in DMF (8 mL) and BocNHNH₂ (2.5 g, 19.12 mmol) wasadded, and then DIPEA (2.5 g, 19.12 mmol) and HATU (3.8 g, 10.04 mmol)were added. The mixture was stirred at rt for 1 hour. Water (30 mL) wasadded and the mixture was extracted with EA (50 mL×3). The combinedorganic phase was dried over anhydrous Na₂SO₄ and concentrated. Theresidue was purified by reverse phase C18 column chromatography to givethe desired product as a yellow solid (2.0 g, 65%).

Example 414 Step b

A solution of tert-butyl 2-(3-fluoro-5-(trifluoromethyl)picolinoyl)hydrazinecarboxylate, prepared in step a, (400 mg, 1.24 mmol)and 1-methoxy-2-methylpropan-2-amine (191 mg, 1.8 mmol) was dissolved inDMSO (10 mL). The mixture was stirred at 100° C. for 4 hours. Water (10mL) was added and it was purified by reverse phase C18 columnchromatography (MeCN/H₂O) to give the desired product as a yellow solid(340 mg, 68%). ESI MS m/z=406.6 [M+H]⁺.

Example 414 Step c

A solution of the compound from step b (340 mg, 0.84 mmol) and ZnBr₂(371 mg, 1.67 mmol) in DCM (10 mL) was stirred for one hour at RT. Itwas concentrated, diluted with 150 ml of EA and washed with water (×3).The organic layer was concentrated to give 1.65 g as a yellow oil. Itwas purified by reverse phase C18 column chromatography (MeCN/H₂O) togive 200 mg of3-((1-methoxy-2-methylpropan-2-yl)amino)-5-(trifluoromethyl)picolinohydrazide.ESI MS m/z=306.5 [M+H]⁺.

Example 414 Step d

Example 414 was prepared using a procedure similar to that used toprepare Example 152 where3-((1-methoxy-2-methylpropan-2-yl)amino)-5-(trifluoromethyl)picolinohydrazidewas used in place of 2-morpholino-4-(trifluoromethyl)benzohydrazide. ESIMS m/z=566.5 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 1.29-1.47 (s, 6H),3.30-3.32 (s, 3H), 3.43-3.53 (s, 2H), 5.18-5.26 (d, J=8.2 Hz, 1H),7.27-7.42 (m, 3H), 7.45-7.64 (m, 5H), 7.66-7.77 (m, 2H), 8.00-8.09 (s,1H), 8.23-8.33 (d, J=1.7 Hz, 1H), 9.48-9.57 (d, J=8.4 Hz, 1H),10.96-11.11 (s, 1H).

Example 415

Example 415 was prepared using a procedure similar to that used toprepare Example 414 where 1-(methoxymethyl)cyclopropan-1-amine was usedin place of 1-methoxy-2-methylpropan-2-amine. ESI MS m/z=564.2 [M+H]⁺.¹H NMR (300 MHz, DMSO-d₆) δ2.38 (3H, d), 2.97 (4H, dd), 3.69 (4H, t),5.12 (1H, d), 6.90 (1H, d), 7.41 (3H, m), 7.67 (5H, m), 8.96 (1H, d),10.96 (1H, s).

Example 416

Example 416 was prepared using a procedure similar to that used toprepare Example 414 where 2-methoxy-2-methylpropan-1-amine was used inplace of 1-methoxy-2-methylpropan-2-amine. ESI MS m/z=555.4 [M+H]⁺. HNMR (300 MHz, DMSO-d₆) δ 1.18 (s, 6H), 3.09 (s, 2H), 3.34 (d, J=4.7 Hz,2H), 5.19 (d, J=8.4 Hz, 1H), 7.21-7.59 (m, 9H), 7.60-7.85 (m, 2H), 8.22(d, J=1.8 Hz, 1H), 9.49 (d, J=8.4 Hz, 1H), 10.99 (s, 1H).

Examples 417 and 418

Examples 417 and 418 were prepared using a procedure similar to thatused to prepare Example 414 where (cis)-2-aminocyclobutanolhydrochloride was used in place of 1-methoxy-2-methylpropan-2-amine. Thecrude product was purified by reverse phase C18 column chromatographyand Prep-HPLC to give 417 as a yellow solid, 14 mg) and 418 as a yellowsolid, 14 mg). Example 417 ESI MS m/z=550.4 [M+H]⁺. ¹H NMR (300 MHz,DMSO-d₆) δ 1.60-1.82 (m, 1H), 1.91 (m, 1H), 2.16 (d, 2H), 4.19 (s, 1H),4.46 (s, 1H), 5.22 (d, 1H), 5.51 (d, 1H), 7.26-7.34 (m, 2H), 7.38 (m,2H), 7.43-7.61 (m, 5H), 7.69 (m, 1H), 8.21-8.38 (m, 2H), 9.49 (d, 1H),11.02 (s, 1H). Example 418 ESI MS m/z=550.4 [M+H]⁺. ¹H NMR (300 MHz,DMSO-d₆) δ 1.72 (m, 1H), 1.91 (m, 1H), 2.05-2.27 (m, 2H), 4.20 (s, 1H),4.46 (s, 1H), 5.22 (d, 1H), 5.51 (d, 1H), 7.25-7.34 (m, 1H), 7.34-7.43(m, 1H), 7.43-7.62 (m, 7H), 7.70 (m, 1H), 8.13-8.55 (m, 2H), 9.50 (d,1H), 11.00 (s, 1H).

Example 419

Example 419 was prepared using a procedure similar to that used toprepare Example 414 where (S)-(tetrahydrofuran-2-yl)methanamine was usedin place of 1-methoxy-2-methylpropan-2-amine. ESI MS m/z=564.2 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 1.60-1.64 (m, 1H), 1.81-1.88 (m, 2H),1.97-2.01 (m, 1H), 3.33-3.37 (m, 1H), 3.51-3.54 (m, 1H), 3.65-3.70 (m,1H), 3.75-3.80 (m, 1H), 4.06-4.09 (m, 1H), 5.20-5.22 (d, J=8.0, 1H),7.27-7.29 (m, 3H), 7.32-7.38 (m, 5H), 7.45-7.49 (m, 1H), 7.51-7.54 (m,1H), 7.61-7.86 (m, 1H), 8.25 (s, 1H), 9.51-9.54 (d, J=12.0, 1H), 10.99(s, 1H).

Example 420

Example 420 was prepared using a procedure similar to that used toprepare Example 414 where (R)-(tetrahydrofuran-2-yl)methanamine was usedin place of 1-methoxy-2-methylpropan-2-amine. ESI MS m/z=564.3 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 1.60-1.64 (m, 1H), 1.81-1.88 (m, 2H),1.97-2.01 (m, 1H), 3.34-3.37 (m, 1H), 3.52-3.55 (m, 1H), 3.65-3.70 (m,1H), 3.74-3.79 (m, 1H), 4.06-4.09 (m, 1H), 5.20-5.22 (d, J=8.0, 1H),7.27-7.29 (m, 3H), 7.32-7.38 (m, 5H), 7.45-7.50 (m, 1H), 7.52-7.54 (m,1H), 7.61-7.86 (m, 1H), 8.26 (s, 1H), 9.51-9.53 (d, J=8.0, 1H), 11.02(s, 1H).

Example 421

Example 421 was prepared using a procedure similar to that used toprepare Example 414 where furan-2-ylmethanamine was used in place of1-methoxy-2-methylpropan-2-amine. ESI MS m/z=560.2 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 4.66-4.68 (d, J=8.0, 1H), 5.18-5.20 (d, J=8.0, 1H),6.40-6.42 (m, 2H), 7.25-7.28 (m, 3H), 7.30-7.36 (m, 5H), 7.43-7.70 (m,3H), 7.99-7.02 (m, 1H), 8.30 (s, 1H), 9.51-9.54 (d, J=12.0, 1H), 11.01(s, 1H).

Example 422

Example 422 was prepared using a procedure similar to that used toprepare Example 414 where (1R,2S)-2-aminocyclopentan-1-ol was used inplace of 1-methoxy-2-methylpropan-2-amine. ESI MS m/z=564.4 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 1.37-1.94 (m, 5H), 1.99-2.16 (m, 1H), 3.84-4.00(m, 1H), 4.06-4.18 (dt, J=7.6, 3.6 Hz, 1H), 4.94-5.03 (d, J=4.5 Hz, 1H),5.16-5.25 (d, J=8.4 Hz, 1H), 7.23-7.44 (m, 3H), 7.41-7.61 (m, 6H),7.63-7.75 (ddd, J=8.3, 7.1, 1.7 Hz, 1H), 8.03-8.12 (d, J=7.4 Hz, 1H),8.18-8.25 (m, 1H), 9.43-9.52 (d, J=8.5 Hz, 1H), 10.99-11.05 (s, 1H).

Example 423

Example 423 was prepared using a procedure similar to that used toprepare Example 414 where (1S,2R)-2-aminocyclopentan-1-ol was used inplace of 1-methoxy-2-methylpropan-2-amine. ESI MS m/z=564.4 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 1.40-1.70 (m, 3H), 1.74-1.80 (s, 1H), 1.80-1.87(s, 1H), 2.03-2.13 (m, 1H), 3.86-3.97 (t, J=6.3 Hz, 1H), 4.07-4.16 (d,J=5.4 Hz, 1H), 4.94-5.03 (d, J=4.5 Hz, 1H), 5.16-5.25 (d, J=8.4 Hz, 1H),7.24-7.42 (m, 3H), 7.42-7.61 (m, 6H), 7.63-7.76 (ddd, J=8.6, 7.0, 1.7Hz, 1H), 8.04-8.13 (d, J=7.5 Hz, 1H), 8.18-8.25 (d, J=1.7 Hz, 1H),9.42-9.51 (d, J=8.4 Hz, 1H), 10.98-11.04 (s, 1H).

Example 424

Example 424 was prepared using a procedure similar to that used toprepare Example 414 where 3-methyltetrahydrofuran-3-amine was used inplace of 1-methoxy-2-methylpropan-2-amine. ESI MS m/z=564.2 [M+H]⁺. HNMR (400 MHz, DMSO-d₆) δ 1.54 (s, 3H), 2.08 (m, 1H), 2.26 (m, 1H), 3.68(d, J=9.3 Hz, 1H), 3.82 (m, 1H), 3.94 (m, 2H), 5.20 (d, J=8.3 Hz, 1H),7.25-7.40 (m, 3H), 7.43-7.63 (m, 6H), 7.69 (m, 1H), 8.10 (s, 1H), 8.32(d, J=1.8 Hz, 1H), 9.58 (d, J=8.4 Hz, 1H), 11.02 (s, 1H).

Example 425

Example 425 Step a

(E)-ethyl 2-cyano-3-ethoxyacrylate (1.37 g, 8.1 mmol) in THF (10 mL) wasdropwised to the solution of 3-hydrazinylpyridine dihydrochloride (1.5g, 8.2 mmol) and NaOEt-EtOH (10.5 g, 32.4 mmol) at 0° C. The mixture wasstirred for 90 minutes at 0° C. 4 M HCl in 1,4-dioxane (8.1 mL, 32.4mmol) was added and the solution was refluxed for 2 hours. The solutionwas concentrated, adjusted pH=10-13 with 1 M NaOH, extracted with EA(×3). The organic layers were combined, dried and concentrated. Thecrude product was purified by reverse phase C18 column chromatography(MeCN/H₂O) to give desired compound as an orange solid (360 mg, 19%).ESI MS m/z=233.3 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 1.31 (m, 3H), 4.27(m, 2H), 5.80 (s, 2H), 7.51 (m, 1H), 8.20 (m, 1H), 8.48 (m, 1H), 8.88(s, 1H), 9.07 (d, J=2.6 Hz, 1H).

Example 425 Step b

NaH (88 mg, 2.21 mmol) was added to the solution of the compound fromstep a (340 mg, 1.47 mmol) in DMF (10 mL) at 0° C. The mixture wasstirred for 40 minutes at 0° C. 1-bromo-2-(2-bromoethoxy)ethane (674 mg,2.93 mmol) was added and then the solution was stirred for 3 hours atrt. The solution was quenched with water, extracted with EA (×3), washedwith brine (×2). The organic layer was dried, concentrated. The residuewas purified via silica gel chromatography (PE-EA) to give ethyl3-morpholino-1-(pyridin-3-yl)-1H-pyrazole-4-carboxylate as yellow solid(180 mg, 41%). ESI MS m/z=303.3 [M+H]⁺.

Example 425 Step c

Example 425 was prepared using a procedure similar to that used toprepare Example 152 where ethyl3-morpholino-1-(pyridin-3-yl)-1H-pyrazole-4-carboxylate was used inplace of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI MSm/z=548.4 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 3.25-3.34 (m, 4H), 3.72(m, 4H), 5.14 (d, J=8.6 Hz, 1H), 7.26-7.44 (m, 3H), 7.45-7.62 (m, 6H),7.69 (m, 1H), 8.26 (m, 1H), 8.52 (m, 1H), 8.97 (s, 1H), 9.03-9.17 (m,2H), 10.99 (s, 1H).

Example 426

Example 426 Step a

A solution of methyl 1H-indole-7-carboxylate (1 g, 5.71 mmol) in DMF (30mL) was added NaH (274 mg, 6.86 mmol) at 0° C. After stirring for 45minutes, 1-bromo-2-methoxyethane (946 mg, 6.86 mmol) was added andstirred for 16 hours at rt. It was quenched with water, extracted withEA (×3), washed with brine (×2). The organic layer was dried, andconcentrated to give the crude methyl1-(2-methoxyethyl)-1H-indole-7-carboxylate as a yellow oil (680 mg,51%). ESI MS m/z=233.9 [M+H]⁺.

Example 426 Step b

Example 426 was prepared using a procedure similar to that used toprepare Example 152 where methyl1-(2-methoxyethyl)-1H-indole-7-carboxylate was used in place of ethyl2-morpholino-4-(trifluoromethyl)benzoate. ESI MS m/z=493.4 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 3.08 (s, 3H), 3.37 (d, J=5.2 Hz, 2H), 4.54 (t,J=5.3 Hz, 2H), 5.20 (d, J=8.6 Hz, 1H), 6.61 (d, J=3.2 Hz, 1H), 7.19 (t,J=7.6 Hz, 1H), 7.26-7.33 (m, 1H), 7.34-7.57 (m, 9H), 7.69 (m, J=8.4,7.1, 1.7 Hz, 1H), 7.80 (m, J=7.9, 1.2 Hz, 1H), 9.14 (d, J=8.6 Hz, 1H),11.01 (s, 1H).

Example 427

Example 427 Step a

A solution of the compound from ethyl2-bromo-5-morpholinothiazole-4-carboxylate, prepared in Example 385,(750 mg, 2.34 mmol), 2-fluorophenylboronic acid (530 mg, 3.51 mmol), Pd(dppf) Cl₂ (188 mg, 0.23 mmol) and Cs₂CO₃ (1395 mg, 4.68 mmol) in DMF(10 mL) was stirred at 80° C. for 4 hrs. Then H₂O (20 mL) was added tothe mixture and extracted with EA (×3). The organic layer was dried andpurified by reverse phase C18 column chromatography to give ethyl2-(2-fluorophenyl)-5-morpholinothiazole-4-carboxylate as yellow oil (680mg, 87%). ESI MS m/z=358.5 [M+H]⁺.

Example 427 Step b

Example 427 was prepared using a procedure similar to that used toprepare Example 152 where ethyl2-(2-fluorophenyl)-5-morpholinothiazole-4-carboxylate was used in placeof ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI MS m/z=582.3[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 3.21-3.23 (m, 4H), 3.73-3.75 (m,4H), 5.16-5.18 (d, J=8.0, 1H), 7.34-7.39 (m, 11H), 7.46-7.53 (m, 1H),8.10-8.20 (m, 1H), 9.16-9.18 (d, J=8.0, 1H), 10.99 (s, 1H).

Example 428

Example 428 was prepared using a procedure similar to that used toprepare Example 390 where 4-fluorophenylboronic acid was used in placeof 6-(trifluoromethyl)pyridin-3-ylboronic acid. ESI MS m/z=582.2 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 3.16-3.18 (m, 4H), 3.73-3.75 (m, 4H),5.15-5.17 (d, J=8.0, 1H), 7.34-7.38 (m, 5H), 7.46-7.48 (m, 6H),7.51-7.53 (m, 1H), 7.90-7.94 (m, 2H), 9.15-9.17 (d, J=8.0, 1H), 10.99(s, 1H).

Example 429

Example 429 was prepared using a procedure similar to that used toprepare Example 390 where 4-pyridylboronic acid was used in place of6-(trifluoromethyl)pyridin-3-ylboronic acid. ESI MS m/z=565.2 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 3.23-3.26 (m, 4H), 3.75-3.76 (m, 4H), 5.16-5.19(d, J=12.0, 1H), 7.35-7.38 (m, 1H), 7.47-7.50 (m, 2H), 7.52-7.54 (m,5H), 7.80 (m, 1H), 7.82 (m, 2H), 8.70-8.72 (m, 2H), 9.20-9.30 (m, 1H),10.99 (s, 1H).

Example 430

Example 430 Step a

NaH (421 mg, 0.011 mol) was added to the solution of ethyl3-amino-1H-pyrazole-4-carboxylate (1.25 g, 0.009 mol) in DMF (5 mL) at0° C. The mixture was stirred for 1 hour at 0° C. Bromocyclobutane (2.16g, 0.016 mol) was added and the mixture was stirred overnight at 50° C.The solution was quenched with water, extracted with EA (×3), washedwith brine (×2), the organic layer was dried, concentrated. The crudeproduct was purified via silica gel chromatography (PE-EA) to givedesired compound as colourless oil (600 mg, 33%). ESI MS m/z=210.3[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 1.24 (m, 3H), 1.73 (m, 2H), 2.27 (m,2H), 2.34-2.50 (m, 2H), 4.16 (m, 2H), 4.61 (m, 1H), 5.38 (s, 2H), 7.95(s, 1H).

Example 430 Step b

A solution of the compound from step a (600 mg, 2.87 mmol),1-bromo-2-(2-bromoethoxy)ethane (1.32 g, 5.74 mmol), Cs₂CO₃ (1.87 g,5.74 mmol) in DMA (10 mL) was stirred overnight at 100° C. The mixturewas diluted with water, extracted with EA (×3). The organic layers werecombined and washed with brine (×2), dried and concentrated. The residuewas purified via silica gel chromatography (PE-EA) to give ethyl1-cyclobutyl-3-morpholino-1H-pyrazole-4-carboxylate as yellow oil (590mg, 74%). ESI MS m/z=280.3 [M+H]⁺.

Example 430 Step c

Example 430 was prepared using a procedure similar to that used toprepare Example 152 where ethyl1-cyclobutyl-3-morpholino-1H-pyrazole-4-carboxylate was used in place ofethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI MS m/z=525.5 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 1.75 (m, 2H), 2.28-2.37 (m, 2H), 2.42-2.48(m, 2H), 3.13-3.21 (m, 4H), 3.67 (m, 4H), 4.79 (m, 1H), 5.10 (d, J=8.7Hz, 1H), 7.25-7.31 (m, 1H), 7.32-7.37 (m, 2H), 7.44-7.56 (m, 5H), 7.67(m, 1H), 8.13 (s, 1H), 8.89 (d, J=8.7 Hz, 1H), 10.96 (s, 1H).

Example 431

Example 431 was prepared using a procedure similar to that used toprepare Example 430 where 2-hydrazinylpyridine dihydrochloride was usedin place of 3-hydrazinylpyridine dihydrochloride. ESI MS m/z=548.3[M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 3.32-3.40 (m, 4H), 5.14 (d, J=8.5Hz, 1H), 7.24-7.39 (m, 4H), 7.42-7.57 (m, 5H), 7.67 (m, 1H), 7.84 (m,1H), 8.00 (m, 1H), 8.45-8.51 (m, 1H), 8.79 (s, 1H), 9.02 (d, J=8.5 Hz,1H), 10.98 (s, 1H).

Example 432

Example 432 Step a

A solution of the compound 4-iodo-tetrahydro-2H-pyran (3.18 g, 15 mmol)was added to ethyl 3-methyl-1H-pyrazole-5-carboxylate (770 mg, 5 mmol)and Cs₂CO₃ in DMF (30 mL) was stirred for 18 hours at 60° C. It wasquenched by H₂O (50 mL) and extracted with EA (3×), dried Na₂SO₄,filtered and purified by reverse phase C18 column chromatography(MeCN/H₂O) to give ethyl3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-5-carboxylate as abrown oil. (143 mg, 12%).

Example 432 Step b

Example 432 was prepared using a procedure similar to that used toprepare Example 152 where ethyl3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-5-carboxylate was usedin place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI MSm/z=484.2 [M+H]⁺. H NMR (300 MHz, Methanol-d₄) δ 1.88-2.02 (m, 2H),2.14-2.35 (m, 5H), 3.58 (m, 2H), 4.08 (m, 2H), 5.19-5.36 (m, 2H), 6.63(s, 1H), 7.25-7.62 (m, 8H), 7.68 (m, 1H).

Example 433

Example 433 Step a

A solution of ethyl 3-chloroquinoxaline-2-carboxylate (500 mg, 2.12mmol) in morpholine (5 mL was stirred for 1 hour at 100° C. It wasdiluted with water, extracted with EA (×3), washed with brine (×2). Theorganic layer was dried and concentrated to give 450 mg (crude) ofdesired compound as yellow oil, which was used directly in the next stepwithout further purification. ESI MS m/z=287.5 [M+H]⁺.

Example 433 Step b

Example 433 was prepared using a procedure similar to that used toprepare Example 152 where ethyl 3-morpholinoquinoxaline-2-carboxylatewas used in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESIMS m/z=533.4 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 3.33-3.49 (m, 4H), 3.76(t, J=4.6 Hz, 4H), 5.25 (d, J=8.4 Hz, 1H), 7.25-7.43 (m, 3H), 7.44-7.63(m, 5H), 7.63-7.77 (m, 2H), 7.77-7.91 (m, 2H), 7.98-8.06 (m, 1H), 9.54(d, J=8.5 Hz, 1H), 11.02 (s, 1H).

Example 434

Example 434 Step a

A solution of the compound 2-chloroquinoline-3-carboxylic acid (414 mg,2 mmol) in MeOH (20 mL) and H₂SO₄ (1 mL) was stirred for 2 hours at 60°C. It was quenched by H₂O (30 mL) at 0° C. and adjusted pH to 8-9,extracted with EA (3×), dried Na₂SO₄, filtered to give desired compoundas a yellow solid (354 mg, 80%). ESI MS m/z=222.2 [M+H]⁺.

Example 435 Step b

A solution of the compound from step a (1.06 g, 3 mmol) in morpholine(20 mL) was stirred for 1 hour at 100° C. Extracted with EA (3×), driedNa₂SO₄, filtered to give desired compound as a light yellow solid (326mg, 75%). ESI MS m/z=273.3 [M+H]⁺.

Example 434 Step c

Example 434 was prepared using a procedure similar to that used toprepare Example 152 where methyl 2-morpholinoquinoline-3-carboxylate wasused in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI MSm/z=532.3 [M+H]⁺. H NMR (300 MHz, DMSO-d₆) δ 3.12-3.30 (m, 4H), 3.73 (m,4H), 5.18 (d, J=8.5 Hz, 1H), 7.21-7.59 (m, 9H), 7.60-7.80 (m, 3H), 7.94(d, J=8.0 Hz, 1H), 8.58 (s, 1H), 9.24 (d, J=8.7 Hz, 1H), 10.98 (s, 1H).

Example 435

Example 435 Step a

6-bromoquinoline-4-carboxylic acid (502 mg, 2.0 mmol), tert-butylhydrazinecarboxylate (528 mg, 4.0 mmol), HATU (836 mg, 2.2 mmol), DIPEA(774 mg, 6.0 mmol) in DMF (5 mL) was stirred for 6 hours at rt. Thesolution was quenched with water, extracted with EA (×3), washed withbrine (×2), the organic layer was dried, concentrated. The crude productwas purified via silica gel chromatography (PE-EA) to give the desiredcompound as yellow solid (680 mg, 93%). ESI MS m/z=367.9 [M+H]⁺.

Example 435 Step b

A solution of the compound from step a (680 mg, 1.86 mmol), Zn(CN)₂ (432mg, 3.72 mmol), Pd(PPh₃)₄ (215 mg, 0.18 mmol) in DMF (5 mL) was stirredfor 2 hours at 120° C. The mixture was diluted with water, extractedwith EA (×3). The organic layers were combined and washed with brine(×2), dried and concentrated. The residue was purified via silica gelchromatography (PE-EA) to give tert-butyl2-(6-cyanoquinoline-4-carbonyl)hydrazine-1-carboxylate as yellow oil(435 mg, 75%). ESI MS m/z=313.0 [M+H]⁺.

Example 435 Step c

Example 435 was prepared using a procedure similar to that used toprepare Example 151 where tert-butyl2-(6-cyanoquinoline-4-carbonyl)hydrazine-1-carboxylate was used in placeof tert-butyl2-(6-fluoro-2-morpholinonicotinoyl)hydrazine-1-carboxylate. ESI MSm/z=472.3 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ5.26-5.29 (d, J=9.0 Hz,1H), 7.28-7.39 (m, 3H), 7.44-7.56 (m, 5H), 7.67-7.72 (m, 1H), 8.01-8.03(m, 1H), 8.17-8.20 (m, 1H), 8.28-8.31 (m, 1H), 9.24-9.26 (d, J=6.0 Hz,1H), 9.61-9.66 (m, 2H), 11.06 (s, 1H).

Example 436

Example 436 was prepared using a procedure similar to that used toprepare Example 420 where trans-4-methoxytetrahydrofuran-3-amine wasused in place of 1-methoxy-2-methylpropan-2-amine. ESI MS m/z=580.1[M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 3.35 (3H, s), 3.69 (2H, m), 3.88(2H, m), 4.05 (1H, dd), 4.33 (1H, d), 5.20 (1H, d), 7.32 (3H, m), 7.51(5H, m), 7.67 (2H, d), 7.80 (1H, d), 8.35 (1H, d), 9.58 (1H, d), 11.02(1H, s).

Example 437

Example 437 Step a

To a stirring solution of ethyl2-bromo-5-morpholinothiazole-4-carboxylate, prepared in Example 385,(400 mg, 1.25 mmol) in toluene (10 mL) was addedtributyl(1-ethoxyvinyl)stannane (905 mg, 2.5 mmol) and Pd(PPh₃)₄ (40 mg,0.001 mmol) at rt under the nitrogen. The mixture was refluxed for 2.5hours at 110° C. under the nitrogen and then concentrated. The reactionmixture was poured into water and extracted with EA (3×100 mL). Theorganic was dried over Na₂SO₄. The residue was purified by silica gelchromatography (PE/EA=3/1) to give the desired compound as a white solid(300 mg, 77%). ESI MS m/z=313.2 [M+H]⁺.

Example 437 Step b

The solution of compound from step a (300 mg, 0.96 mmol) was added tothe HCl (5 mL) in the dioxane (8 mL) at rt. The resulting solution wasstirred at rt for 5 hrs. The reaction mixture was poured into saturatedNaHCO₃ liquid and extracted with EA (3×100 mL). The organic layer wasdried over Na₂SO₄ and purified to give the desired compound product as awhite solid (150 mg, 55%). ESI MS m/z=285.4 [M+H]⁺.

Example 437 Step c

To a stirred solution of the compound from step b (200 mg, 0.7 mmol) inTHF (6 mL) was added MeMgCl (0.27 ml, 0.77 mmol). The mixture wasstirred at rt for 2.5 hours under the nitrogen and then concentrated.The reaction mixture was poured into ice water and extracted with EA(3×60 mL). The organic layer was dried over Na₂SO₄ and purified byreverse phase C18 column chromatography (ACN/H₂O=1/5) to give thedesired compound as a off white solid (175 mg, 83%). ESI MS m/z=301.1[M+H]⁺.

Example 437 Step d

Example 437 was prepared using a procedure similar to that used toprepare Example 152 where ethyl2-(2-hydroxypropan-2-yl)-5-morpholinothiazole-4-carboxylate was used inplace of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI MSm/z=456.2 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ1.48 (4H, s), 3.02 (3H, d),3.67 (3H, d), 5.12 (1H, s), 7.32 (2H, d), 7.49 (5H, d), 8.35 (1H, d).

Example 438

Example 438 Step a

NaH (61.5 mg, 1.54 mol) was added to the solution of ethyl4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylate (250 mg, 1.28mmol) in DMF (5 mL) at 0° C. The mixture was stirred for 1 hour at 0°.1-Bromo-2-methoxyethane (353 mg, 2.56 mmol) was added and the mixturewas stirred overnight. The solution was quenched with water, extractedwith EA (×3), washed with brine (×2), the organic layer was dried,concentrated. The crude product was purified via silica gelchromatography (PE-EA) to give desired compound as yellow oil (260 mg,80%). ESI MS m/z=254.3 [M+H]⁺.

Example 438 Step b

Example 438 was prepared using a procedure similar to that used toprepare Example 152 where ethyl4-(2-methoxyethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylatewas used in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESIMS m/z=499.5 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 2.03 (m, 2H), 3.18 (s,3H), 3.37 (s, 2H), 3.41 (m, 2H), 3.79 (m, 2H), 4.02 (m, 2H), 5.09 (d,J=8.7 Hz, 1H), 7.24-7.32 (m, 1H), 7.34 (m, 2H), 7.43-7.58 (m, 6H), 7.67(m, 1H), 8.76 (d, J=8.7 Hz, 1H), 10.95 (s, 1H).

Example 439

Example 439 Step a

3-Azabicyclo[3.1.0]hexan-6-ol (220 mg, 1.62 mmol) was dissolved in THF(5 mL) and K₂CO₃ (289.8 mg, 2.1 mmol) was added. CbzCl (360 mg, 2.1mmol) was then added and the mixture was stirred at rt overnight. Waterwas added and the mixture was extracted with EA. The combined organicphase was dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by silica gel chromatography (PE:EA=10:1) to give the desiredproduct as a white solid (250 mg, 66%). ESI MS m/z=234.2 [M+H]⁺.

Example 439 Step b

The compound from step a (250 mg, 1.07 mmol) was dissolved in DCM (8 mL)and cooled with ice bath. The proton sponge (689 mg, 3.21 mmol) wasadded and then trimethyloxonium tetrafluoroborate (238 mg, 1.6 mmol) wasadded. The mixture was warmed to rt and stirred overnight. Water wasadded and the mixture was extracted with EA. The combined organic phasewas dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by Prep-TLC (PE:EA=2:1) to give the desired product as a yellowoil (121 mg, 46%) and the starting material (50 mg, 0.21 mmol). ESI MSm/z=248.3 [M+H]⁺.

Example 439 Step c

The compound from step b (121 mg, 0.49 mmol) was dissolved in MeOH (10mL) and Pd/C (20 mg) was added. The mixture was exchanged with H₂ threetimes and then stirred overnight. The mixture was filtered and thefiltrate was concentrated to give 6-methoxy-3-azabicyclo[3.1.0]hexane asa white solid (30 mg, 55%). There was no signal on LCMS of the product.

Example 439 Step d

Example 439 was prepared using a procedure similar to that used toprepare Example 414 where 6-methoxy-3-azabicyclo[3.1.0]hexane was usedin place of 1-methoxy-2-methylpropan-2-amine. ESI MS m/z=576.5 [M+H]⁺.¹H NMR (300 MHz, DMSO-d₆) δ ¹H NMR (300 MHz, DMSO-d₆) δ 3.24 (s, 3H),3.26-3.31 (m, 2H), 5.20 (d, J=8.4 Hz, 1H), 7.18-7.40 (m, 3H), 7.40-7.61(m, 6H), 7.68 (t, J=7.9 Hz, 1H), 8.37 (s, 1H), 9.26 (d, J=8.5 Hz, 1H),11.00 (s, 1H).

Example 440

Example 440 Step a

A solution of ethyl 3-amino-1H-pyrazole-4-carboxylate (1.55 g, 0.01mol), 2-bromo-5-(trifluoromethyl)pyridine (2.25 g, 0.01 mol), Cs₂CO₃(6.52 g, 0.02 mol) in DMF (20 mL) was stirred for 1 hour at 100° C. Themixture was diluted with water, extracted with EA (×3). The organiclayers were combined and washed with brine (×2), dried, concentrated.The crude product was purified via silica gel chromatography (PE-EA) togive desired compound as yellow solid (1.95 g, 65%). ESI MS m/z=301.2[M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 1.31 (m, 3H), 4.14-4.40 (m, 2H),5.96 (d, J=4.0 Hz, 2H), 7.86 (m, 1H), 8.36 (m, 1H), 8.74 (d, J=3.7 Hz,1H), 8.83 (d, J=2.8 Hz, 1H).

Example 440 Step b

NaH (360 mg, 0.015 mol) was added to the solution of the compound fromstep a (1.95 g, 6.5 mmol) and 1-bromo-2-(2-bromoethoxy)ethane (1.645 g,7.2 mmol) in DMF (20 mL) at 0° C. The mixture was stirred overnight atr.t. The mixture was quenched with water, extracted with EA (×3). Theorganic layers were combined and washed with brine (×2), dried andconcentrated. The crude product was purified via silica gelchromatography (PE-EA) to give desired compound as yellow solid (350 mg,15%). ESI MS m/z=371.2 [M+H]⁺.

Example 440 Step c

Example 440 was prepared using a procedure similar to that used toprepare Example 152 where ethyl3-morpholino-1-(5-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-4-carboxylatewas used in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESIMS m/z=616.4 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 3.39 (m, 4H), 3.67-3.85(m, 4H), 5.16 (d, J=8.5 Hz, 1H), 7.25-7.40 (m, 3H), 7.45-7.62 (m, 5H),7.65-7.73 (m, 1H), 8.01 (d, J=8.7 Hz, 1H), 8.41 (m, 1H), 8.87 (s, 1H),8.88-8.96 (m, 1H), 9.10 (d, J=8.5 Hz, 1H), 11.01 (s, 1H).

Example 441

Example 441 was prepared using a procedure similar to that used toprepare Example 435 where 5-bromopyrazolo[1,5-a]pyridine-3-carboxylicacid was used in place of 6-bromoquinoline-4-carboxylic acid. ESI MSm/z=461.3[M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ5.18-5.20 (d, J=6.0 Hz, 1H),7.27-7.39 (m, 1H), 7.43-7.46 (m, 2H), 7.49-7.54 (m, 6H), 7.66-7.71 (m,1H), 8.64-8.70 (m, 2H), 9.01-9.11 (m, 2H), 10.70 (s, 1H).5-bromopyrazolo[1,5-a]pyridine-3-carboxylic acid.

Examples 442 and 443

Examples 442 and 443 Step a

A 2M solution of trimethylaluminum in hexanes (23 mL, 44.40 mmol) wasadded to a mixture of N,O-dimethylhydroxylamine hydrochloride (4.3 g,44.40 mmol) in DCM (30 mL) and the reaction was stirred at 0° C. for 40mins. A solution of 3-morpholino-5-(trifluoromethyl)picolinic acid (9 g,29.60 mmol) in DCM (20 mL) was added and the reaction mixture wasstirred at 40° C. for 2 hours. After cooling to r.t., the mixture wascarefully quenched with 1N HCl and diluted with DCM. After 30 minstirring layers were separated and the organic layers were washed withbrine, dried over anhydrous Na₂SO₄ and concentrated to give the desiredcompound as a yellow solid (9 g, 95%). ESI MS m/z=320.3[M+H]⁺.

Examples 442 and 443 Step b

A solution of the (3 M) MeMgCl (10.3 mL, 31 mmol) in hexane wasdropwised to the compound from step a (9 g, 28.20 mmol) in THF at 0° C.under N₂. It was stirred for 2 hours at 0° C. The mixture was dilutedwith EA and quenched with sat. NH₄Cl, the organic layers were washedwith brine, dried over anhydrous Na₂SO₄ and concentrated to give thedesired compound as a yellow oil (7.2 g, 93%). ESI MS m/z=275.2 [M+H]⁺.

Examples 442 and 443 Step c

HBr-AcOH was added to a solution of the compound from step b (7.20 g,26.3 mmol) in AcOH (20 mL), Then pyridinium tribromide (9.20 g, 28.9mmol) was added at rt. It was stirred for 2 hours at rt and filtered.The solid was washed with AcOH and partitioned between EA/sat NaHCO₃,the organic layers were washed with brine, dried over anhydrous Na₂SO₄and concentrated to give the desired compound as a yellow solid (6.1 g,66%). ESI MS m/z=355.1 [M+H]⁺.

Examples 442 and 443 Step d

A solution of the compound from step 3 (3 g, 8.52 mmol), NaN₃ (0.61 g,9.38 mmol) in acetone/H₂O=2/1 (15 mL) was stirred for 1 hour at rt. Themixture was diluted with EA, washed by brine. The organic phase wasdried over anhydrous Na₂SO₄ and concentrated to 10 ml in EA. It was usedfor next step directly. ESI MS m/z=316.1 [M+H]⁺.

Examples 442 and 443 Step e

TCDI (1.97 g, 11.08 mmol) was added to a solution of the compound(Z)-3-amino-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one (2.14 g, 8.52mmol) in DCM (10 mL). It was stirred for 20 mins. The mixture wasdiluted with DCM, washed by brine. The organic phase was dried overanhydrous Na₂SO₄ and concentrated to give the isothiocyanateintermediate. A solution of the compound from step d in EA was added tothe isothiocyanate and PPh₃ (2.70 g, 10.20 mmol) in dioxane under N₂.The mixture was stirred at 90° C. for 40 mins then at rt overnight. Thesolvents were removed and purified by reverse phase C18 columnchromatography (MeCN/H₂O) to give desired compound as yellow solid. (230mg, 4%). ESI MS m/z=583.4 [M+H]⁺.

Examples 442 and 443 Step f

EDCI (260 mg, 1.37 mmol) was added to a solution of the compound fromstep e (230 mg, 0.34 mmol) in DMF. It was stirred for 5 hours at 90° C.The crude product was purified by Prep-HPLC (MeCN/H₂O) to give desiredcompound as yellow solid (70 mg, 38%). ESI MS m/z=549.4 [M+H]⁺.

Examples 442 and 443 Step g

The compound from step f (70 mg, 0.13 mmol) was purified byPrep-Chiral-HPLC to give the title compound 442 (21 mg, 29%) as yellowsolid and 443 (22 mg, 31%) as yellow solid. Example 442 ESI MS m/z=549.4[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 2.94 (m, 4H), 3.77 (m, 4H), 5.26 (d,J=8.5 Hz, 1H), 7.25-7.31 (m, 1H), 7.34 (m, 2H), 7.42-7.60 (m, 5H), 7.67(m, 1H), 7.84 (d, J=2.1 Hz, 2H), 8.58-8.71 (m, 1H), 9.20 (d, J=8.6 Hz,1H), 10.93 (s, 1H). Example 443 ESI MS m/z=549.4 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 2.94 (m, 4H), 3.77 (m, 4H), 5.26 (d, J=8.5 Hz, 1H),7.23-7.32 (m, 1H), 7.34 (m, 2H), 7.41-7.58 (m, 5H), 7.67 (m, 1H), 7.84(d, J=2.0 Hz, 2H), 8.63 (m, 1H), 9.20 (d, J=8.6 Hz, 1H), 10.93 (s, 1H).

Examples 444 and 445

Examples 444 and 445 Step a

A solution of ethyl 3-amino-1H-pyrazole-4-carboxylate (1.55 g, 0.01mol), 5-fluoro-2-(trifluoromethyl)pyridine (1.65 g, 0.01 mol), Cs₂CO₃(4.89 g, 0.015 mol) in DMF (8 mL) was stirred for 1 hour at 100° C. Themixture was diluted with water, extracted with EA (×3). The organiclayers were combined and washed with brine (×2), dried, concentrated.The crude product was purified via silica gel chromatography (PE-EA) togive the mixture of desired compounds as a yellow solid (1.04 g, 35%).ESI MS m/z=301.1[M+H]⁺.

Examples 444 and 445 Step b

NaH (168 mg, 4.2 mmol) was added to the solution of the compound fromstep a (1.04 g, 3.5 mmol) and 1-bromo-2-(2-bromoethoxy)ethane (966 mg,4.2 mmol) in DMF (20 mL) at 0° C. The mixture was stirred overnight. Themixture was quenched with water, extracted with EA (×3). The organiclayers were combined and washed with brine (×2), dried, concentrated.The crude product was purified via silica gel chromatography (PE-EA) togive the mixture of desired compounds as a white solid (280 mg, 22%).ESI MS m/z=371.2 [M+H]⁺.

Examples 444 and 445 Step c

Examples 444 and 445 were prepared using a procedure similar to thatused to prepare Example 152 where ethyl3-morpholino-1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-4-carboxylateand ethyl5-morpholino-1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-4-carboxylatewere used in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate.The isomers were separated by prep HPLC (MeCN/H₂O/0.1% FA). Example 444ESI MS m/z=616.5 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 3.31 (m, 4H), 3.74(m, 4H), 5.16 (d, J=8.5 Hz, 1H), 7.25-7.42 (m, 3H), 7.51 (m, J 5H),7.65-7.74 (m, 1H), 8.07 (d, J=8.7 Hz, 1H), 8.51 (m, 1H), 9.09-9.16 (m,2H), 9.32 (d, J=2.5 Hz, 1H), 11.00 (s, 1H). Example 445 ESI MS m/z=616.5[M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 3.14 (m, 4H), 3.59 (m, 4H), 5.17 (d,J=8.4 Hz, 1H), 7.26-7.41 (m, 3H), 7.44-7.61 (m, 5H), 7.64-7.73 (m, 1H),8.11-8.20 (m, 2H), 8.50 (m, 1H), 9.12-9.21 (m, 2H), 11.01 (s, 1H).

Examples 446 and 447

Examples 446 and 447 Step a

NaH (1.6 g, 0.04 mol) was added to the solution of ethyl3-amino-1H-pyrazole-4-carboxylate (3.10 g, 0.02 mol) in DMF (25 mL) at0° C. Then (bromomethyl)cyclopropane (2.68 g, 0.02 mol) was added. Themixture was stirred for 3 hours at rt. The solution was quenched withwater, extracted with EA (×3), washed with brine (×2), the organic layerwas dried, concentrated. The crude product was purified via silica gelchromatography (PE-EA) to give desired compound as a yellow oil (1.81 g,43%). ESI MS m/z=209.9 [M+H]⁺.

Examples 446 and 447 Step b

A solution of the compound from step a (1.81 g, 8.66 mmol),1-bromo-2-(2-bromoethoxy)ethane (6.0 g, 25.98 mmol) and Cs₂CO₃ (5.64 g,17.32 mmol) in DMA (20 mL) was stirred for 4 hours at 100° C. Themixture was diluted with water, extracted with EA (×3). The organiclayers were combined and washed with brine (×2), dried, andconcentrated. The residue was purified via silica gel chromatography(PE-EA) to give desired compound as off-white solid (1.08 g, 45%). ESIMS m/z=280.0 [M+H]⁺.

Examples 446 and 447 Step c

A solution of the compound from step b (1.08 g, 3.87 mmol) andNH₂NH₂.H₂O (10 mL) in EtOH (20 mL) was refluxed for 3 hours. The crudeproduct was purified by Prep-HPLC (MeCN/H₂O) to give desired compound asyellow oil (810 mg, 79%). ESI MS m/z=260.0 [M+H]⁺.

Examples 446 and 447 Step d

A solution of (Z)-3-amino-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one(753 mg, 3.0 mmol), and di (1H-imidazol-1-yl)methanethione (1.6 g, 9.0mmol) in DMF (10 mL) was stirred for 1 hour at 0° C. and the compoundfrom step c (810 mg, 3.05 mmol) was added to the solution and stirred atrt for 2 hours. The residue was purified by Prep-HPLC (MeCN/H₂O) to givedesired compound as a yellow solid (950 mg, 57%). ESI MS m/z=559.3[M+H]⁺.

Examples 446 and 447 Step e

EDCI (980 mg, 5.10 mmol) was added to the solution of the compound fromstep d (950 mg, 1.70 mmol) in DMF (5 mL). The mixture was stirred at 60°C. for 2 hours. The mixture was diluted with water, extracted with DCM(×3). The organic layers were combined and dried, concentrated. Theresidue was then purified by preparative TLC (EA) and Prep-HPLC(MeCN/H2O/0.1% FA) to give the desired compound as a yellow solid (500mg, 56%). ESI MS m/z=525.3 [M+H]⁺.

Examples 446 and 447 Step f

The compound from step e (500 mg, 0.95 mmol) was separated bychiral-HPLC to give 446 as a off-white solid (101 mg) and 447 as ayellow solid (162 mg). Example 446: ESI MS m/z=525.5 [M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 0.35-0.39 (m, 2H), 0.51-0.57 (m, 2H), 1.24-1.28 (m, 1H),3.17-3.18 (m, 4H), 3.66-3.67 (m, 4H), 3.89-3.91 (m, 2H), 5.08-5.11 (d,J=9.0 Hz, 1H), 7.26-7.36 (m, 3H), 7.44-7.54 (m, 5H), 7.65-7.70 (m, 1H),8.10 (s, 1H), 8.88-8.91 (d, J=9.0 Hz, 1H), 10.96 (s, 1H). Example 447:ESI MS m/z=525.4 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 0.36-0.38 (m, 2H),0.52-0.55 (m, 2H), 1.08-1.40 (m, 1H), 3.17-3.18 (m, 4H), 3.66-3.68 (m,4H), 3.89-3.91 (m, 2H), 5.08-5.11 (d, J=9.0 Hz, 1H), 7.28 (m, 3H),7.33-7.36 (m, 5H), 7.46-7.52 (m, 1H), 8.10 (s, 1H), 8.88-8.91 (d, J=9.0Hz, 1H), 10.96 (s, 1H).

Example 448

Example 448 was prepared using a procedure similar to that used toprepare Example 448 where 2,5-difluoropyridine was used in place of2-bromo-5-(trifluoromethyl)pyridine. ESI MS m/z=566.3 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆) δ 3.31 (m, 4H), 3.73 (m, 4H), 5.14 (d, J=8.0 Hz, 1H),7.25-7.38 (m, 3H), 7.42-7.61 (m, 5H), 7.68 (m, 1H), 7.89 (m, 1H), 7.97(m, 1H), 8.52 (d, J=2.9 Hz, 1H), 8.74 (s, 1H), 9.06 (d, J=8.6 Hz, 1H).

Example 449

Example 449 Step a

A solution of ethyl 5-bromopyrazolo[1,5-a]pyridine-3-carboxylate (1.0 g,3.73 mmol), methylboronic acid (448 mg, 7.46 mmol), Pd(dppf)Cl₂ (545 mg,0.746 mmol) and Cs₂CO₃ (2.42 g, 7.46 mmol) was dissolved in DMF (5.0mL), then the mixture was stirred at 100° C. for two hours. It wasconcentrated, and purified by silica gel chromatography with PE:EA=5:1to obtain the desired compound as an orange solid (589 mg, 77%). ESI MSm/z=204.5 [M+H]⁺.

Example 449 Step b

A solution of the compound from step a (434 mg, 2.13 mmol), BPO (515 mg,2.13 mmol), and NBS (398 mg, 2.24 mmol) was dissolved in CCl₄ (6 mL) atrt, then the mixture was stirred at 78° C. for one hour. Aftercompletion, the mixture was quenched with water, and extracted with EA(20 mL×2), the organic layer was combined, washed with water, saturatedsolution of NaHCO₃ (15 mL) and brine (15 mL) in turn, then dried withanhydrous Na₂SO₄ and concentrated to obtain a yellow solid (415 mg, 69%)that was used without further purification. ESI MS m/z=282.3 [M+H]⁺.

Example 449 Step c

A mixture of NaH (96 mg, 3.99 mmol) in MeOH (5 mL) was stirred at 0° C.for 5 minutes, then the compound from step b (375 mg, 1.33 mmol) wasadded to the mixture. It was heated to 50° C. for one hour. Aftercompletion, the mixture was poured into ice-water solution of glacialacetic acid, and extracted with EA (25 mL×2), the organic layer wascombined, washed with brine (15 mL), then dried with anhydrous Na₂SO₄and concentrated to obtain methyl5-(methoxymethyl)pyrazolo[1,5-a]pyridine-3-carboxylate as a light yellowsolid that was used without further purification. ESI MS m/z=220.5[M+H]⁺.

Example 449 Step d

Example 449 was prepared using a procedure similar to that used toprepare Example 152 where methyl5-(methoxymethyl)pyrazolo[1,5-a]pyridine-3-carboxylate was used in placeof ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI MS m/z=480.3[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 3.38 (s, 3H), 4.56 (s, 2H), 5.17 (d,1H), 7.04 (m, 1H), 7.25-7.33 (m, 1H), 7.37 (m, 2H), 7.42-7.58 (m, 5H),7.69 (m, 1H), 7.95-8.04 (m, 1H), 8.42 (s, 1H), 8.84 (d, 1H), 8.98 (d,1H), 10.90 (s, 1H).

Example 450

Example 450 Step a

A solution of ethyl 3-chloro-5-(trifluoromethyl)pyridine-2-carboxylate(700 mg, 2.76 mmol),2-[(E)-2-ethoxyethenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (545 mg,2.75 mmol), Pd(dppf)Cl₂ (197 mg, 0.27 mmol) and Cs₂CO₃ (2.7 g, 8.29mmol) in 1,4-dioxane (15 mL) and water (5 mL) was stirred for 1 hour at80° C. The reaction was then diluted by the addition of water. Theresulting solution was extracted with EA. The crude product was purifiedby reverse phase C18 column chromatography to give the desired compound(550 mg, 69%) as off-white oil. ESI MS m/z=290.1 [M+H]⁺.

Example 450 Step b

A solution of compound from step a (400 mg, 1.38 mmol), HCl-dioxane (2mL, 4N) in dioxane (2 mL) was stirred for 2 hours at rt. The reactionwas then quenched by the addition of NaHCO₃ and extracted with of DCM.The organic layers combined and dried over anhydrous sodium sulfate andconcentrated under vacuum to give the desired compound (388 mg, 107%) asa yellow oil that was used without further purification. ESI MSm/z=262.0 [M+H]⁺.

Example 450 Step c

A solution of compound from step b (380 mg, 1.45 mmol) in THF (6 mL) wasadded BH₃.THF (2.9 mL, 2.9 mmol) dropwise at 0° C. It was stirred for 30min at 0° C. The reaction was then quenched by the addition of water andextracted with DCM. The organic layers combined and concentrated undervacuum. The organic layer was purified by silica gel column to give thedesired compound 160 mg as off-white oil. ESI MS m/z=264.1 [M+H]⁺.

Example 450 Step d

A solution of compound from step c (160 mg, 0.61 mmol), NH₂NH₂.H₂O (2mL) in EtOH (2 mL) was stirred for 1 hour at 80° C. The reaction wasthen washed by the addition of water and extracted with of DCM. Theorganic layers combined and concentrated under vacuum to give3-(2-hydroxyethyl)-5-(trifluoromethyl)picolinohydrazide (100 mg, 66%) asoff-white oil. ESI MS m/z=250.0 [M+H]⁺.

Example 450 Step e

Example 450 was prepared using a procedure similar to that used toprepare Example 21 where3-(2-hydroxyethyl)-5-(trifluoromethyl)picolinohydrazide was used inplace of tetrahydro-2H-pyran-4-carbohydrazide. ESI MS m/z=509.2 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 3.30 (d, J=6.1 Hz, 2H), 3.70 (q, J=5.8, 5.8,5.6 Hz, 2H), 4.69 (t, J=5.3, 5.3 Hz, 1H), 5.21 (d, J=6.5 Hz, 1H),7.23-7.41 (m, 3H), 7.43-7.59 (m, 5H), 7.63-7.79 (m, 1H), 8.25 (d, J=2.2Hz, 1H), 8.92-9.05 (m, 1H), 9.38-9.56 (m, 1H), 10.98 (s, 1H).

Example 451

Example 451 was prepared using a procedure similar to that used inExample 339 where (R)-1-methoxypropan-2-amine was used in place ofmorpholine. ESI MS m/z=558.2 [M+H]⁺.

Example 452

Example 452 was prepared using a procedure similar to that used inExample 339 where (S)-2-methoxypropan-1-amine was used in place ofmorpholine. ESI MS m/z=558.2 [M+H]⁺.

Example 453

Example 453 Step a

Example 453 step a was prepared using a procedure similar to that usedto prepare Example 345 where ethyl5-bromo-2-(trifluoromethyl)thiazole-4-carboxylate was used in place ofmethyl 5-bromo-2-methylthiazole-4-carboxylate.

Example 453 Step b

Example 453 step b was prepared using a procedure similar to that usedto prepare Example 152 where ethyl5-(3,6-dihydro-2H-pyran-4-yl)-2-(trifluoromethyl)thiazole-4-carboxylatewas used in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESIMS m/z=553.1 [M+H]⁺.

Example 454

Example 454 Step a

To a oven-dried round-bottomed flask, 2,2,3,3,3-pentafluoropropanamide(2 g, 12.27 mmol) was dissolved in THF (29.9 mL) under nitrogen to givea color solution. Lawesson's reagent (2.98 g, 7.36 mmol) was added tothe reaction mixture. Stir reaction vessel at 80° C. overnight. Thereaction mixture was cooled and ethyl 3-bromo-2-oxopropanoate (1.92 mL,15.33 mmol) was added. The flask was again heated to 80° C. and stirredovernight. The mixture was poured into water and the aqueous layer wasextracted with EtOAc. The organic layer was dried, filtered andconcentrated. The crude product was added to a silica gel column and waseluted with ethyl acetate/hexane 0% to 50% to give ethyl2-(perfluoroethyl)thiazole-4-carboxylate (1.29 g, 38% yield) as a whitesolid.

Example 454 Step b

A solution of ethyl 2-(perfluoroethyl)thiazole-4-carboxylate (1.29 g,4.69 mmol) in THF (10.7 mL) was added to LDA (2.93 mL, 5.86 mmol) in THF(32.0 mL) at −78° C. under N₂. The mixture was stirred for 45 minutes atsame temperature. To this, a solution of 1,2-dibromotetrachloroethane(2.29 g, 7.03 mmol) in THF (10.7 mL) was dropwised and warmed to roomtemperature over 2 hours. The reaction was quenched with saturatedammonium chloride solution. Water was added and the mixture wasextracted with ethyl acetate (3×). The organic layer was combined, driedand concentrated. The crude product was added to a silica gel column andwas eluted with ethyl acetate/hexane 0% to 50% to give ethyl5-bromo-2-(perfluoroethyl)thiazole-4-carboxylate (0.894 g, 54% yield) asa white solid.

Example 454 Step c

Example 454 was prepared using a procedure similar to that used toprepare Example 272 where ethyl5-bromo-2-(perfluoroethyl)thiazole-4-carboxylate was used in place ofmethyl 2-methyl-5-bromothiazole-4-carboxylate. ESI-MS m/z: 606.1 [M+H]⁺.

Example 455

Example 455 Step a

To a cold (−78° C.) solution of ethyl 5-morpholinothiazole-4-carboxylate(0.5 g, 2.06 mmol) in THF (5.2 mL) was added n-BuLi (1.29 mL, 2.06 mmol)dropwise. The reaction was stirred for 15 minutes and cyclobutanone(0.15 mL, 2.06 mmol) was added via syringe. The reaction was stirred for1 hour and was then quenched by the addition of saturated aqueousbicarbonate solution. The cold bath was removed and the reaction waswarmed to room temperature. Ethyl acetate was added and the layers wereseparated. The aqueous layer was extracted with additional ethyl acetate(2×). The combined organics were dried with anhydrous sodium sulfate,filtered and concentrated under reduced pressure to give the crude titlecompound. The crude product was added to a silica gel column and waseluted with ethyl acetate/hexane 0% to 50% to give ethyl2-(1-hydroxycyclobutyl)-5-morpholinothiazole-4-carboxylate (427 mg, 66%yield) as a yellow solid.

Example 455 Step b

Example 455 was prepared using a procedure similar to that used toprepare Example 152 where ethyl2-(1-hydroxycyclobutyl)-5-morpholinothiazole-4-carboxylate was used inplace of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI MSm/z=558.2 [M+H]⁺.

Example 456

Example 456 was prepared using a procedure similar to that used toprepare Example 21 where ethyl(R)-5-(2-(methoxymethyl)pyrrolidin-1-yl)-2-(trifluoromethyl)thiazole-4-carboxylate,which was prepared similarly to ethyl5-morpholino-2-(trifluoromethyl)thiazole-4-carboxylate in Example 339,was converted to the corresponding hydrazide and used in oftetrahydro-2H-pyran-4-carbohydrazide. The racemic mixture was purifiedby chiral separation. (Column=YMC CHIRAL Cellulose-SB, 250*20 mm (5 uM);Mobile Phase=50% iPrOH/50% hexanes; Flow rate=20 mL/min). ESI MSm/z=584.2 [M+H]⁺.

Example 457

Example 457 was prepared using a procedure similar to that used toprepare Example 21 where ethyl(S)-5-(2-(methoxymethyl)pyrrolidin-1-yl)-2-(trifluoromethyl)thiazole-4-carboxylate,which was prepared similarly to ethyl5-morpholino-2-(trifluoromethyl)thiazole-4-carboxylate in Example 339,was converted to the corresponding hydrazide and used in place oftetrahydro-2H-pyran-4-carbohydrazide. The racemic mixture was purifiedby chiral separation. (Column=YMC CHIRAL Cellulose-SB, 250*20 mm (5 uM);Mobile Phase=50% iPrOH/50% hexanes; Flow rate=20 mL/min). ESI MSm/z=584.2 [M+H]⁺.

Example 458

Example 458 Step a

Example 458 step a was prepared using a procedure similar to that usedto prepare Example 454 where 1-fluorocyclobutane-1-carboxamide was usedin place of 2,2,3,3,3-pentafluoropropanamide to give ethyl2-(1-fluorocyclobutyl)thiazole-4-carboxylate.

Example 458 Step b

Ethyl 2-(1-fluorocyclobutyl)thiazole-4-carboxylate (230 mg, 1.0 mmol)was taken up in MeOH (2 mL) and 1M NaOH (2 mL) and stirred at roomtemperature for 30 mins. The reaction mixture was concentrated and theaqueous layer was extracted 3× with EtOAc. The organic layer was dried,filtered and concentrated. 2-(1-fluorocyclobutyl)thiazole-4-carboxylicacid (197 mg, 98% yield) was isolated as a white solid.

A solution of 2-(1-fluorocyclobutyl)thiazole-4-carboxylic acid (197 mg,0.98 mmol) in Tetrahydrofuran (11.5 mL) was cooled to −78° C. underargon and treated with a n-butyllithium (1.29 mL, 2.06 mmol). Thereaction mixture was left to warm to room temperature over 15 minutes,then cooled again to −78° C. A solution of bromine (55 μL, 1.08 mmol) inhexane (0.5 mL) was added. The reaction mixture was left to warm to roomtemperature, then quenched by addition of 1N HCl. The mixture wasextracted three times with methylene chloride, and the combined organiclayers were dried over sodium sulphate and evaporated. The crude productwas added to a silica gel column and was eluted withmethanol/dichloromethane 0% to 10% to give5-bromo-2-(1-fluorocyclobutyl)thiazole-4-carboxylic acid (219 mg, 80%yield) as a white solid.

Example 458 Step c

To a vial, 5-bromo-2-(1-fluorocyclobutyl)thiazole-4-carboxylic acid (218mg, 0.78 mmol), HATU (355 mg, 0.93 mmol) and tert-butylhydrazinecarboxylate (123 mg, 0.93 mmol) was dissolved in DMF (7.2 mL)open to air to give a yellow solution. DIPEA (272 μL, 1.56 mmol) wasadded to the reaction mixture in one portion. Stir at room temperaturefor 2 hours. Concentrate reaction mixture and load crude reactionmixture on to silica gel plug. The crude product was added to a silicagel column and was eluted with ethyl acetate/hexane 0% to 50% to givetert-butyl2-(5-bromo-2-(1-fluorocyclobutyl)thiazole-4-carbonyl)hydrazine-1-carboxylate(270 mg, 88% yield) as a white solid.

Example 458 Step d

To a oven-dried vial, tert-butyl2-(5-bromo-2-(1-fluorocyclobutyl)thiazole-4-carbonyl)hydrazine-1-carboxylate(270 mg, 0.69 mmol) was dissolved in morpholine (1370 μL) open to air togive a color suspension. K₂CO₃ (189 mg, 1.37 mmol) was added to thereaction mixture. Stir at 80° C. for 3 hours. Filtered and washed withDCM and concentrate the organic layer. The crude product was added to asilica gel column and was eluted with ethyl acetate/hexane 0% to 50% togive ethyl tert-butyl2-(2-(1-fluorocyclobutyl)-5-morpholinothiazole-4-carbonyl)hydrazine-1-carboxylate(198 mg, 72% yield) as a white solid.

Example 458 Step e

A solution of tert-butyl2-(2-(1-fluorocyclobutyl)-5-morpholinothiazole-4-carbonyl)hydrazine-1-carboxylate(198 mg, 0.49 mmol) and hydrochloric acid, 37% (1.12 mL) in EtOH (11.2mL) was stirred at room temperature for 1 hour. It was adjusted topH=7-8 with saturated aqueous NaHCO₃. Extract with DCM (3×). Dry andconcentrate organic layer. The crude product was added to a silica gelcolumn and was eluted with methanol/dichloromethane 0% to 10% to give2-(1-ethoxycyclobutyl)-5-morpholinothiazole-4-carbohydrazide (51 mg, 32%yield) as a white solid.

Example 458 Step f

Example 458 was prepared using a procedure similar to that used toprepare Example 21 where2-(1-ethoxycyclobutyl)-5-morpholinothiazole-4-carbohydrazide was used inplace of tetrahydro-2H-pyran-4-carbohydrazide. The racemic mixture waspurified by chiral separation. (Column=YMC CHIRAL Cellulose-SB, 250*20mm (5 uM); Mobile Phase=50% i-PrOH/50% hexanes; Flow rate=20 mL/min).ESI MS m/z=586.2 [M+H]⁺.

Example 459

Example 459 Step a

To a oven-dried vial, tert-butyl2-(5-bromo-2-(2-fluoropropan-2-yl)thiazole-4-carbonyl)hydrazine-1-carboxylate(166 mg, 0.43 mmol) was dissolved in Morpholine (0.87 mL) open to air togive a yellow suspension. K₂CO₃ (120 mg, 0.87 mmol) was added to thereaction mixture and allowed to stir at 90° C. for four hours. Thereaction mixture was filtered and washed with DCM. The filtrate wasconcentrated. The crude product was added to a silica gel column and waseluted with ethyl acetate/hexane 0% to 50% to give ethyl tert-butyl2-(5-morpholino-2-(2-morpholinopropan-2-yl)thiazole-4-carbonyl)hydrazine-1-carboxylate(180 mg, 91% yield) as a white solid.

Example 459 Step b

To a vial, tert-butyl2-(5-morpholino-2-(2-morpholinopropan-2-yl)thiazole-4-carbonyl)hydrazine-1-carboxylate(180 mg, 0.395 mmol) was taken up in DCM (0.6 mL) and TFA (0.6 mL). Stirreaction at room temperature for 1 hour. Reaction mixture wasconcentrated and taken up in DCM and sat. aq. NaHCO₃ (aq). The aqueouslayer was extracted with DCM (2×). The organic layer was dried, filteredand concentrated.5-morpholino-2-(2-morpholinopropan-2-yl)thiazole-4-carbohydrazide (135mg, 96% yield) was taken forward without purification.

Example 459 Step c

Example 459 was prepared using a procedure similar to that used toprepare Example 21 where5-morpholino-2-(2-morpholinopropan-2-yl)thiazole-4-carbohydrazide wasused in place of tetrahydro-2H-pyran-4-carbohydrazide. The racemicmixture was purified by chiral separation. (Column=YMC CHIRALCellulose-SB, 250*20 mm (5 uM); Mobile Phase=50% i-PrOH/50% hexanes;Flow rate=20 mL/min). ESI MS m/z=528.2 [M-C₄H₉NO]⁺.

Example 460

Example 460 step a was prepared using a procedure similar to 458 where1-(trifluoromethyl)cyclopropane-1-carboxamide was used in place of1-fluorocyclobutane-1-carboxamide. The racemic mixture was purified bychiral separation. (Column=YMC CHIRAL Cellulose-SB, 250*20 mm (5 uM);Mobile Phase=50% EtOH/50% hexanes; Flow rate=20 mL/min). ESI MSm/z=596.2 [M+H]⁺.

Example 461

Example 461 Step a

An oven dried vial was charged with methyl5-bromo-3-morpholinopicolinate (340 mg, 1.13 mmol), cesium fluoride (858mg, 5.65 mmol), and copper (I) iodide (1402 mg, 11.29 mmol). The vialwas purged with nitrogen gas, then NMP (20 mL) was added via syringe. Tothis mixture was added (difluoromethyl)trimethylsilane (1402 mg, 11.29mmol). The reaction mixture was heated at 120° C. for 24 hours. Aftercooling to rt, the reaction mixture was filtered through a pad of silicagel and washed with EtOAc (50 mL). The filtrate was concentrated andpurified by RP-HPLC (30-95% MeCN:water) to provide methyl5-(difluoromethyl)-3-morpholinopicolinate (30 mg, 10% yield) as a yellowoil. ESI MS m/z=273.1 [M+H]⁺.

Example 461 Step b

Example 461 was prepared using a procedure similar to that used toprepare Example 152 where methyl5-(difluoromethyl)-3-morpholinopicolinate was used in place of ethyl2-morpholino-4-(trifluoromethyl)benzoate. ESI MS m z=596.2 [M+H]⁺.

Example 462

Example 462 Step a

An oven dried vial was charged with 3,5-dichloropyridazine (100 mg, 0.67mmol), phenylboronic acid (82 mg, 0.671 mmol), potassium fluoride (97mg, 1.68 mmol), palladium acetate (8 mg, 0.034 mmol), and Q-Phos (24 mg,0.034 mmol). The vial was purged with nitrogen gas, then toluene (5 mL)and water (1.2 mL) were added via syringe. The reaction mixture washeated at 70° C. for 22 hours. After cooling to rt, the reaction mixturewas diluted with EtOAc (4 mL). The reaction mixture was filtered througha pad of celite and concentrated. The residue was purified on silica gel(0-100% EtOAc:hexanes) to provide 3-chloro-5-phenylpyridazine (110 mg,86% yield) as a tan solid. ESI MS m/z=191.1 [M+H]⁺.

Example 462 Step b

An oven dried vial was charged with 3-chloro-5-phenylpyridazine (80 mg,0.420 mmol), 3-amino-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one(158 mg, 0.629 mmol), potassium tert-butoxide (141 mg, 1.259 mmol),SPhos (17 mg, 0.042 mmol), and SPhos-palladium G3 (33 mg, 0.042 mmol).The vial was purged with nitrogen gas, then tert-butanol was added (10mL). The reaction mixture was heated at 60° C. for 90 min. After coolingto rt, the reaction mixture was filtered through a pad of silica gel andconcentrated. The residue was purified on silica gel (0-10% MeOH:DCM) toprovide the product as a tan solid (25 mg, 15% yield). ESI MS m/z=406.1[M+H]⁺.

Example 463

Example 463 Step a

An oven dried vial was charged with 3,5-dichloropyridazine (115 mg,0.772 mmol). The vial was purged with nitrogen gas, then MeCN (5 mL) wasadded via syringe. Morpholine (0.22 mL, 2.57 mmol) was added dropwise at0° C. The reaction mixture was stirred at rt for 1 h, then concentrated.The residue was purified by RP-HPLC (60-100% MeCN:water) to provide4-(6-chloropyridazin-4-yl)morpholine as a yellow oil (115 mg, 75%yield). ESI MS m/z=200.2 [M+H]⁺.

Example 463 Step b

An oven dried vial was charged with 4-(6-chloropyridazin-4-yl)morpholine(120 mg, 0.601 mmol),3-amino-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one (76 mg,0.301 mmol), potassium tert-butoxide (101 mg, 0.902 mmol), andSPhos-palladium G3 (12 mg, 0.015 mmol). The vial was purged withnitrogen gas, then tert-butanol was added (5 mL). The reaction mixturewas heated at 80° C. for 20 hours. After cooling to rt, the reactionmixture was filtered through a pad of silica gel and concentrated. Theresidue was purified by RP-HPLC (30-100% MeCN:water) to provide theproduct as a tan solid (20 mg, 16% yield). ESI MS m/z=415.1 [M+H]⁺.

Example 464

Example 464 was prepared using a procedure similar to that used toExample 160 where (R)-tetrahydrofuran-3-amine and ethyl3-chloro-5-(trifluoromethyl)picolinate were used in place of morpholineand methyl 5-bromo-3-fluoropicolinate, respectively. ESI MS m/z=550.1M+H]⁺.

Example 465

Example 465 was prepared using a procedure similar to that used toprepare Example 430 where ethyl5-amino-3-methylisothiazole-4-carboxylate was used in place of ethyl3-amino-1-cyclobutyl-1H-pyrazole-4-carboxylate. ESI MS m/z=502.1 [M+H]⁺.

Example 466

Example 466 was prepared using a procedure similar to that used toExample 160 where 2-oxa-5-azabicyclo[4.1.0]heptane and ethyl3-chloro-5-(trifluoromethyl)picolinate were used in place of morpholineand methyl 5-bromo-3-fluoropicolinate, respectively. ESI MS m/z=562.1[M+H]⁺.

Example 467

Example 467 was prepared using a procedure similar to that used toExample 160 where 2-(trifluoromethyl)morpholine and ethyl3-chloro-5-(trifluoromethyl)picolinate were used in place of morpholineand methyl 5-bromo-3-fluoropicolinate, respectively. ESI MS m/z=618.1[M+H]⁺.

Example 468

Example 468 was prepared using a procedure similar to that used toExample 160 where 3,4-dihydro-2H-benzo[b][1,4]oxazine and ethyl3-chloro-5-(trifluoromethyl)picolinate were used in place of morpholineand methyl 5-bromo-3-fluoropicolinate, respectively. ESI MS m/z=598.1[M+H]⁺.

Example 469

Example 469 was prepared using a procedure similar to that used toExample 160 where oxetan-3-amine and ethyl3-chloro-5-(trifluoromethyl)picolinate were used in place of morpholineand methyl 5-bromo-3-fluoropicolinate, respectively. ESI MS m/z=536.1[M+H]⁺.

Example 470

Example 470 was prepared using a procedure similar to that used toExample 160 where (S)-tetrahydrofuran-3-amine and ethyl3-chloro-5-(trifluoromethyl)picolinate were used in place of morpholineand methyl 5-bromo-3-fluoropicolinate, respectively. ESI MS m/z=550.1[M+H]⁺.

Example 471

Example 471 was prepared using a procedure similar to that used toprepare Example 430 where ethyl 2-aminothiophene-3-carboxylate was usedin place of ethyl 3-amino-1-cyclobutyl-1H-pyrazole-4-carboxylate. ESI MSm/z=487.1 [M+H]⁺.

Example 472

Example 472 was prepared using a procedure similar to that used toprepare Example 471 where 1-bromo-2-methoxyethane was used in place of1-bromo-2-(2-bromoethoxy)ethane. ESI MS m/z=475.1 [M+H]⁺.

Example 473

Example 473 was prepared using a procedure similar to that used inExample 339 where 2-methoxyethan-1-amine was used in place ofmorpholine. ESI MS m/z=544.1[M+H]⁺.

Example 474

Example 474 was prepared using a procedure similar to that used inExample 339 where (R)-tetrahydrofuran-3-amine was used in place ofmorpholine. ESI MS m/z=556.1 [M+H]⁺.

Example 475

Example 475 was prepared using a procedure similar to that used inExample 339 where oxetan-3-ylmethanamine was used in place ofmorpholine. ESI MS m/z=556.1 [M+H]⁺.

Example 476

Example 476 Step a

To an 8 mL vial 4-fluoro-2-hydroxybenzonitrile (150 mg, 1.094 mmol) wasdissolved in acetone (2188 μL). To the solution was added ethyl2-bromoacetate (121 μL, 1.094 mmol) followed by potassium carbonate (151mg, 1.094 mmol). The vial was sealed with electrical tape and heated to40° C. for 12 h. The reaction was allowed to cool to room temperatureand water (2 mL) and EtOAc (2 mL) were added. The organic layer wasseparated and the aqueous layer was washed with EtOAc (2×2 mL). Thecombined organic layer was dried over MgSO₄ and concentrated. The crudereaction mixture was purified by silica gel chromatography (80:20Hex/EtOAc). The desired product, ethyl3-amino-6-fluorobenzofuran-2-carboxylate, was obtained as a white solid(186 mg, 76% yield).

Example 476 Step b

Example 476 was prepared using a procedure similar to that used toprepare Example 430 where ethyl 3-amino-6-fluorobenzofuran-2-carboxylatewas used in place of ethyl3-amino-1-cyclobutyl-1H-pyrazole-4-carboxylate. ESI MS m/z=539.2 [M+H]⁺.

Example 477

Example 477 was prepared using a procedure similar to that used toprepare Example 476 where 2-fluoro-6-hydroxybenzonitrile was used inplace of 4-fluoro-2-hydroxybenzonitrile. ESI MS m/z 10=539.2 [M+H]⁺.

Example 478

Example 478 was prepared using a procedure similar to 458 where1-methylcyclobutane-1-carboxamide was used in place of1-fluorocyclobutane-1-carboxamide. The racemic mixture was purified bychiral separation. (Column=YMC CHIRAL Cellulose-SB, 250*20 mm (5 uM);Mobile Phase=50% EtOH/50% hexanes; Flow rate=20 mL/min). ESI MSm/z=556.3 [M+H]⁺.

Example 479

Example 479 Step a

To an nitrogen-sparged solution of methyl methyl5-bromo-2-methylthiazole-4-carboxylate (0.5 g, 2.012 mmol),(E)-2-(3-methoxyprop-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(1.068 ml, 5.03 mmol), and potassium phosphate (1.525 g, 7.04 mmol) indry THF (20 mL) was added tetrakis(triphenylphosphine)palladium(0)(0.470 g, 0.402 mmol). After an additional 2 min sparging, the mixturewas stirred at 66° C. for 16 h at which time it was diluted with water(20 mL) and extracted 3× with ethyl acetate. The combined organics werewashed with brine, dried over anhydrous MgSO₄, filtered, andconcentrated in vacuo. The resulting residue was flash chromatographedon silica gel to afford methyl(E)-5-(3-methoxyprop-1-en-1-yl)-2-methylthiazole-4-carboxylate (310.1mg, 1.364 mmol, 67.8% yield) (TLC 30% EtOAc in hexanes, rf ˜0.2) as ayellowish oil.

Example 479 Step b

An oven dried 20 mL vial was charged with methyl(E)-5-(3-methoxyprop-1-en-1-yl)-2-methylthiazole-4-carboxylate (257 mg,1.131 mmol), palladium on carbon (120 mg, 0.113 mmol) and anhydrous MeOH(11.308 mL). The flask was then purged with hydrogen and then stirredunder hydrogen atm at rt overnight. The solvent was evaporated and thecrude residue filtered through a plug of silica gel using 1:1EtOAc:hexanes as the eluent. Then the crude residue was purified throughcolumn chromatography to yield methyl5-(3-methoxypropyl)-2-methylthiazole-4-carboxylate (195.1 mg, 0.851mmol, 75% yield) as a colorless oil.

Example 479 Step c

Example 479 was prepared using a procedure similar to that used toprepare Example 152 where methyl5-(3-methoxypropyl)-2-methylthiazole-4-carboxylate was used in place ofethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI MS m/z=489.2 [M+H]⁺.

Examples 480, 481, 482, and 483

Examples 480, 481, 482, and 483 Step a

Et₂Zn (1 M in Hexane) (10.4 mL, 10.4 mmol) was added to thePH-ETA-A1-770-1 (0.3 g, 1.04 mmol) at 0° C., then CH₂I₂ (5.6 g, 20.8mmol) was added under N₂. The mixture was stirred for 1 day at rt. Thereaction mixture was quenched with saturated aqueous ammonium chloridesolution and extracted with EtOAc. The organic layer was washed withbrine, dried over sodium sulfate and concentrated. The crude product waspurified by silica gel chromatography (PE-EA) and chiral-Prep-HPLC togive desired compound as yellow oil (0.23 g, 73%). ESI MS m/z=304.3[M+H]⁺.

Examples 480, 481, 482, and 483 Step b

A solution of the compound from step a (230 mg, 0.76 mmol) andNH₂NH₂.H₂O (2 mL) in EtOH (5 mL) was stirred for 1 hour at r.t. Thecrude product was purified by Flash-Prep-HPLC (MeCN/H₂O) to give desiredmixture of compounds as a yellow oil (150 mg, 68%). The mixture wasseparated by chiral-Prep-HPLC to give A (67 mg, 45%) and B (70 mg, 47%).A: ESI MS m/z=290.3 [M+H]⁺. B: ESI MS m/z=290.3 [M+H]⁺.

Examples 480, 481, 482, and 483 Step c

Examples 480 and 481 (with hydrazide A from step b), and 482 and 483(with hydrazide B from step b), were prepared using a procedure similarto that used to prepare Example 21 where hydrazide A and hydrazide Bwere used in place of tetrahydro-2H-pyran-4-carbohydrazide. Compounds481 and 482 were separated by chiral-Prep-HPLC. Compounds 483 and 484were separated by chiral-Prep-HPLC. Example 480: ESI MS m/z=549.5[M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 1.05 (m, 1H), 1.19 (m, 1H), 1.58 (m,1H), 2.90 (m, 1H), 3.23 (s, 3H), 3.28 (d, J=6.5 Hz, 1H), 3.46 (m, 1H),5.22 (d, J=8.2 Hz, 1H), 7.24-7.42 (m, 3H), 7.41-7.61 (m, 5H), 7.68 (m,1H), 7.83-7.93 (m, 1H), 8.83-9.04 (m, 1H), 9.44 (d, J=8.4 Hz, 1H), 11.00(s, 1H). Example 481: ESI MS m/z=549.4 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆)δ 1.05 (m, 1H), 1.13-1.28 (m, 1H), 1.51-1.67 (m, 1H), 2.90 (m, 1H), 3.23(s, 3H), 3.26-3.31 (m, 1H), 3.46 (m, 1H), 5.22 (d, J=8.3 Hz, 1H),7.24-7.41 (m, 3H), 7.42-7.60 (m, 5H), 7.68 (m, 1H), 7.88 (d, J=2.2 Hz,1H), 8.84-9.08 (m, 1H), 9.44 (d, J=8.3 Hz, 1H), 11.00 (s, 1H). Example482: ESI MS m/z=549.4 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 1.05 (m, 1H),1.13-1.27 (m, 1H), 1.50-1.67 (m, 1H), 2.89 (m, 1H), 3.23 (s, 3H),3.25-3.31 (m, 1H), 3.45 (m, 1H), 5.22 (d, J=8.4 Hz, 1H), 7.25-7.40 (m,3H), 7.43-7.58 (m, 5H), 7.68 (m, 1H), 7.82-7.94 (m, 1H), 8.91 (m, 1H),9.45 (d, J=8.4 Hz, 1H), 11.01 (s, 1H). Example 483: ESI MS m/z=549.5[M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 0.98-1.10 (m, 1H), 1.19 (m, 1H),1.50-1.65 (m, 1H), 2.90 (m, 1H), 3.23 (s, 3H), 3.28 (m, 1H), 3.45 (m,1H), 5.22 (d, J=8.4 Hz, 1H), 7.24-7.40 (m, 3H), 7.42-7.58 (m, 5H), 7.68(m, 1H), 7.84-7.89 (m, 1H), 8.91 (m, 1H), 9.45 (d, J=8.4 Hz, 1H), 11.00(s, 1H).

Examples 484, 485, 486, and 487

Examples 484, 485, 486, and 487 Step a

A solution of ethyl 2-(trifluoromethyl)thiazole-4-carboxylate (1.3 g,5.78 mmol) in THF (5 mL) was dropwised to the solution of LDA (5.8 mL,11.56 mmol) in THF (10 mL) at −78° C. under N₂. The mixture was stirredfor 45 minutes at same temperature. To this, a solution of1,2-dibromo-1,1,2,2-tetrachloroethane (5.58 g, 17.34 mmol) in THF (5 mL)was dropwised and warmed to room temperature, stirred for 2 hours. Thereaction was quenched with saturated ammonium chloride solution. Waterwas added and the mixture was extracted with EA (×3). The organic layerwas combined, dried and concentrated. The residue was purified viasilica gel chromatography (petroleum ether-ethyl acetate) to give thedesired compound as yellow oil (900 mg, 51%). ESI MS m/z=549.5 [M+H]⁺.

Examples 484, 485, 486, and 487 Step b

A solution of the compound from step a (800 mg, 2.64 mmol),2-oxa-5-aza-bicyclo[4.1.0]heptane hydrochloride (535 mg, 3.96 mmol) andDIPEA (0.8 mL) in DMSO (4 mL) was stirred overnight at 80° C. It wasextracted with EA (25 mL×2), combined the organic layer, and dried withanhydrous Na₂SO₄, then concentrated and purified by silica gel column togive the mixture of enantiomers as an orange oil (443 mg, 52%). Themixture was purified by chiral-Prep-HPLC to give A (200 mg, 42%) and B(210 mg, 44%). ESI MS m/z=549.5 [M+H]⁺.

Examples 484, 485, 486, and 487 Step c

Examples 484 and 485 (with ester A from step b), and 486 and 487 (withester B from step b), were prepared using a procedure similar to thatused to prepare Examples 480, 481, 482, and 483. Example 484: ESI MSm/z=568.4 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 0.81 (m, 2H), 2.94 (m,2H), 3.56-3.83 (m, 3H), 3.88 (m, 1H), 5.15 (d, 1H), 7.13-7.41 (m, 3H),7.41-7.61 (m, 5H), 7.61-7.83 (m, 1H), 9.14 (d, 1H), 10.97 (s, 1H).Example 485: ESI MS m/z=568.4 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 0.82(s, 2H), 2.92 (m, 2H), 3.57-4.02 (m, 4H), 5.15 (d, 1H), 7.32 (m, 3H),7.51 (m, 5H), 7.67 (m, 1H), 9.14 (d, 1H), 10.97 (s, 1H). Example 486:ESI MS m/z=568.4 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 0.73-0.92 (m, 2H),2.92 (m, 2H), 3.64 (m, 1H), 3.67-3.82 (m, 2H), 3.89 (m, 1H), 5.15 (d,1H), 7.19-7.39 (m, 3H), 7.39-7.59 (m, 5H), 7.68 (m, 1H), 9.14 (d, 1H),10.97 (s, 1H). Example 487: ESI MS m/z=568.4 [M+H]⁺. ¹H NMR (300 MHz,DMSO-d₆) δ 0.82 (m, 2H), 2.93 (m, 2H), 3.65 (m, 1H), 3.68-3.81 (m, 2H),3.89 (m, 1H), 5.15 (d, 1H), 7.14-7.40 (m, 3H), 7.40-7.59 (m, 5H), 7.68(m, 1H), 9.14 (d, 1H), 10.97 (s, 1H).

Examples 488 and 489

Examples 488 and 489 Step a

To a stirred solution of the ethyl 3-amino-1H-pyrazole-4-carboxylate (4g, 0.025 mol) in DMF (50 mL) was added Cs₂CO₃ (8.2 g, 0.025 mol) and1,1,1-trifluoro-2-iodoethane (10.5 g, 0.055 mol) at it. The mixture wasstirred at 70° C. over the night and then concentrated. The reactionmixture was filtered and the filtrate was poured into water andextracted with EA (3×150 mL). The organic layer was dried over Na₂SO₄.The residue was purified via silica gel chromatography (petroleumether-ethyl acetate) to give the desired compound as a yellow solid (2.5g, 44%). ESI MS m/z=238.2 [M+H]⁺.

Examples 488 and 489 Step b

To a stirred solution of the compound from step 1 (2.5 g, 0.011 mol) inthe DMA (30 mL) was added to 1-bromo-2-(2-bromoethoxy) ethane (5.82 g,0.025 mol) and Cs₂CO₃ (5.5 g, 0.017 mol) at rt. The resulting solutionwas stirred at 100° C. for 6 hours and then concentrated. The reactionmixture was poured into water and extracted with EA (3×150 ml). Theorganic layer was dried over Na₂SO₄. The residue was purified via silicagel chromatography (petroleum ether-ethyl acetate) to give the desiredproduct as a yellow solid (700 mg, 21%). ESI MS m/z=308.4 [M+H]⁺.

Examples 488 and 489 Step c

To a stirring solution of the compound from step 2 (700 mg, 3.74 mmol)in EtOH (5 mL) was added NH₂NH₂.H₂O (4 mL) at rt. The resulting solutionwas stirred at rt for 5 hours. The reaction mixture was purified byreverse phase C18 column chromatography (MeCN:H₂O) (MeCN/H₂O) to givethe desired product as a yellow solid (300 mg, 27%). ESI MS m/z=294.1[M+H]⁺.

Examples 488 and 489 Step d

Examples 488 and 489 were prepared using a procedure similar to thatused to prepare Example 21 where3-morpholino-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carbohydrazide wasused in place of tetrahydro-2H-pyran-4-carbohydrazide. Examples 488 and489 were separated by chiral-Prep-HPLC. Example 488: ESI MS m/z=553.0[M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ3.12-3.23 (dd, J=6.1, 3.4 Hz, 4H),3.61-3.82 (m, 4H), 5.00-5.23 (m, 3H), 7.26-7.39 (m, 3H), 7.39-7.59 (m,5H), 7.64-7.76 (m, J=8.5, 7.0, 1.8 Hz, 1H), 8.16-8.32 (s, 1H), 8.93-9.12(d, J=8.7 Hz, 1H), 10.90-11.12 (s, 1H). Example 489: ESI MS m/z=553.0[M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ3.10-3.26 (dd, J=6.1, 3.4 Hz, 4H),3.61-3.78 (m, 4H), 5.00-5.18 (dd, J=8.8, 3.4 Hz, 3H), 7.13-7.38 (m, 3H),7.39-7.62 (m, 5H), 7.65-7.76 (m, J=8.5, 7.0, 1.8 Hz, 1H), 8.16-8.29 (s,1H), 8.95-9.10 (d, J=8.6 Hz, 1H), 10.83-11.10 (s, 1H).

Example 490

Example 490 was prepared using a procedure similar to 458 where1-(trifluoromethyl)cyclobutane-1-carboxamide was used in place of1-fluorocyclobutane-1-carboxamide. The racemic mixture was purified bychiral separation. (Column=YMC CHIRAL Cellulose-SB, 250*20 mm (5 uM);Mobile Phase=50% EtOH/50% hexanes; Flow rate=20 mL/min). ESI MSm/z=610.2 [M+H]⁺.

Example 491

Example 491 was prepared using a procedure similar to 430 wherebromocyclopentane was used in place of bromocyclobutane. ESI MSm/z=539.5 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 1.55-1.69 (m, 2H), 1.77(m, 2H), 1.84-1.96 (m, 2H), 1.96-2.10 (m, 2H), 3.02-3.26 (m, 4H), 3.66(m, 4H), 4.63 (m, 1H), 5.10 (d, J=8.7 Hz, 1H), 7.23-7.39 (m, 3H),7.41-7.58 (m, 5H), 7.67 (m, 1H), 8.06 (s, 1H), 8.85 (d, J=8.7 Hz, 1H),10.96 (s, 1H).

Example 492

Example 492 was prepared using a procedure similar to 458 where MeOH wasused in place of EtOH in step e. The racemic mixture was purified bychiral separation. (Column=YMC CHIRAL Cellulose-SB, 250*20 mm (5 uM);Mobile Phase=50% EtOH/50% hexanes; Flow rate=20 mL/min). ESI MSm/z=572.2 [M+H]⁺.

Example 493

Example 493 was prepared using a procedure similar to that used toprepare Example 21 where ethyl(R)-5-((5-oxopyrrolidin-3-yl)amino)-2-(trifluoromethyl)thiazole-4-carboxylate,which was prepared similarly to ethyl5-morpholino-2-(trifluoromethyl)thiazole-4-carboxylate in Example 339,was converted to the corresponding hydrazide and used in place oftetrahydro-2H-pyran-4-carbohydrazide. The racemic mixture was purifiedby chiral separation. (Column=YMC CHIRAL Cellulose-SB, 250*20 mm (5 uM);Mobile Phase=50% iPrOH/50% hexanes; Flow rate=20 mL/min). ESI MSm/z=569.1 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 2.33 (dd, J=16.7, 5.3 Hz,1H), 2.69 (dd, J=16.7, 7.9 Hz, 1H), 3.28 (dd, J=10.2, 4.5 Hz, 1H), 3.70(dd, J=10.1, 7.0 Hz, 1H), 4.23 (q, J=6.1, 6.1, 6.0 Hz, 1H), 5.15 (d,J=8.4 Hz, 1H), 7.24-7.39 (m, 3H), 7.42-7.58 (m, 5H), 7.68 (ddd, J=8.4,7.0, 1.8 Hz, 1H), 7.81 (s, 1H), 9.15 (d, J=8.6 Hz, 1H), 10.95 (s, 1H).

Example 494

Example 494 was prepared using a procedure similar to that used toprepare Example 21 where ethyl(R)-5-((2-oxopyrrolidin-3-yl)amino)-2-(trifluoromethyl)thiazole-4-carboxylate,which was prepared similarly to ethyl5-morpholino-2-(trifluoromethyl)thiazole-4-carboxylate in Example 339,was converted to the corresponding hydrazide and used in place oftetrahydro-2H-pyran-4-carbohydrazide. The racemic mixture was purifiedby chiral separation. (Column=YMC CHIRAL Cellulose-SB, 250*20 mm (5 uM);Mobile Phase=50% iPrOH/50% hexanes; Flow rate=20 mL/min). ESI MSm/z=569.1 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 2.03 (dq, J=12.2, 9.6,9.6, 9.6 Hz, 1H), 2.62 (dt, J=12.6, 6.6, 6.6 Hz, 1H), 3.30 (d, J=3.4 Hz,2H), 4.26 (t, J=9.3, 9.3 Hz, 1H), 5.16 (d, J=8.4 Hz, 1H), 7.19-7.43 (m,3H), 7.40-7.76 (m, 7H), 8.21 (s, 1H), 9.14 (d, J=8.5 Hz, 1H), 10.98 (s,1H).

Example 495

Example 495 Step a

A solution of ethyl 5-bromo-2-(trifluoromethyl)thiazole-4-carboxylate(500 mg, 1.65 mmol), LiOH (198 mg, 8.25 mmol) in THF (5 mL) and H₂O (2mL) was stirred for 1 hour at RT. It was adjusted pH value to 4 with 3 NHCl and purified by Flash (MeCN/H₂O) to give the desired acid as yellowsolid (410 mg, 90.3%). The acid (410 mg, 1.49 mmol), K₂CO₃ (411 mg, 2.98mmol), BnBr (507 mg, 2.98 mmol) in DMF (5 mL) was stirred for 1 hour atRT and purified by Flash (MeCN/H₂O) to give the desired compound asyellow solid (505 mg, 92.8%). The compound had no signal on LCMS.

Example 495 Step b

A solution of the compound from step 1 (580 mg, 1.59 mmol),morpholin-3-one (481 mg, 4.76 mmol), Pd₂(dba)₃ (164 mg, 0.15 mmol),Xantphos (184 mg, 0.31 mmol), Cs₂CO₃ (1.03 g, 3.18 mmol) in 1,4-dioxane(10 mL) was stirred at 100° C. for 2 hours. The solution wasconcentrated and purified by TLC give the desired product as yellowsolid (140 mg, 22.81%). ESI MS m/z=409.1 [M+H]⁺.

Example 495 Step c

A solution of the compound from step 2 (140 mg, 0.36 mmol), Pd/C (50 mg)in MeOH (10 mL) under H₂ was stirred at RT for 2 hours. The solid wasfiltered out and concentrated to give5-(3-oxomorpholino)-2-(trifluoromethyl)thiazole-4-carboxylic acid asyellow solid (70 mg, 65.69%). ESI MS m/z=297.2 [M+H]⁺.

Example 495 Step d

A solution of the compound from step 3 (70 mg, 0.23 mmol), tert-butylhydrazinecarboxylate (62 mg, 0.46 mmol), HATU (131 mg, 0.34 mmol), DIPEA(0.5 mL) in DMF (2 mL) was stirred at RT for 2 hours. The solution waspurified by Flash (MeCN/H₂O) to give the desired product as yellow oil(50 mg, 53.02%). ESI MS m/z=354.9 [M-t-Bu]⁺.

Example 495 Step e

A solution of the compound from step 4 (50 mg, 0.12 mmol), TFA (2 mL) inDCM (16 mL) was stirred at RT for 1 hour. The solution was adjusted pHvalue to 10 with Sat. NaHCO₃solution and purified by Flash (MeCN/H₂O) togive 5-(3-oxomorpholino)-2-(trifluoromethyl)thiazole-4-carbohydrazide asyellow solid (25 mg, 67.56%). ESI MS m/z=310.5 [M+H]⁺.

Example 495 Step f

Example 495 was prepared using a procedure similar to that used toprepare Example 21 where5-(3-oxomorpholino)-2-(trifluoromethyl)thiazole-4-carbohydrazide wasused in place of tetrahydro-2H-pyran-4-carbohydrazide. The racemicmixture was purified by chiral separation. (Column=YMC CHIRALCellulose-SB, 250*20 mm (5 uM); Mobile Phase=50% iPrOH/50% hexanes; Flowrate=20 mL/min). ESI MS m/z=570.1 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ3.82-3.84 (m, 2H), 3.99-4.03 (m, 2H), 4.32 (s, 2H), 5.16-5.19 (d, J=9.0Hz, 1H), 7.27-7.36 (m, 3H), 7.43-7.53 (m, 5H), 7.64-7.67 (m, 1H),9.43-9.46 (d, J=9.0 Hz, 1H), 10.98 (s, 1H).

Example 496

Example 496 was prepared using a procedure similar to that used toprepare Example 430 where 1-bromo-2-methoxyethane was used in place of1-bromo-2-(2-bromoethoxy)ethane. ESI MS m/z=513.4 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 1.65-1.84 (m, 2H), 2.31 (m, 2H), 2.40-2.48 (m, 2H), 3.27(s, 3H), 3.39 (m, 2H), 3.51 (m, 2H), 4.72 (m, 1H), 5.10 (d, J=8.6 Hz,1H), 5.40 (s, 1H), 7.24-7.31 (m, 1H), 7.32-7.38 (m, 2H), 7.43-7.57 (m,5H), 7.67 (m, 1H), 7.99 (s, 1H), 8.85 (d, J=8.7 Hz, 1H), 10.97 (s, 1H).

Example 497

Example 497 was prepared using a procedure similar to 458 where3,3,3-trifluoro-2,2-dimethylpropanamide was used in place of1-fluorocyclobutane-1-carboxamide. The racemic mixture was purified bychiral separation. (Column=YMC CHIRAL Cellulose-SB, 250*20 mm (5 uM);Mobile Phase=50% EtOH/50% hexanes; Flow rate=20 mL/min). ESI MSm/z=598.2 [M+H]⁺.

Example 498

Example 498 was prepared using a procedure similar to 458 where3,3,3-trifluoro-2,2-dimethylpropanamide and 2-methoxyethan-1-amine wereused in place of 1-fluorocyclobutane-1-carboxamide and morpholine,respectively. The racemic mixture was purified by chiral separation.(Column=YMC CHIRAL Cellulose-SB, 250*20 mm (5 uM); Mobile Phase=50%EtOH/50% hexanes; Flow rate=20 mL/min). ESI MS m/z=586.2 [M+H]⁺.

Example 499

Example 499 was prepared using a procedure similar to that used toprepare Example 21 where ethyl(R)-5-((tetrahydro-2H-pyran-3-yl)amino)-2-(trifluoromethyl)thiazole-4-carboxylate,which was prepared similarly to ethyl5-morpholino-2-(trifluoromethyl)thiazole-4-carboxylate in Example 339,was converted to the corresponding hydrazide and used in place oftetrahydro-2H-pyran-4-carbohydrazide. The racemic mixture was purifiedby chiral separation. (Column=YMC CHIRAL Cellulose-SB, 250*20 mm (5 uM);Mobile Phase=50% iPrOH/50% hexanes; Flow rate=20 mL/min). ESI MSm/z=570.1 [M+H]⁺.

Examples 500-518

The following compounds are prepared according to the general methoddescribed in Examples 430, 458 and 499.

Example 500

Example 501

Example 502

Example 503

Example 504

Example 505

Example 506

Example 507

Example 508

Example 509

Example 510

Example 511

Example 512

Example 513

Example 514

Example 515

Example 516

Example 517

Example 518

Assays Methods for RSV-A Assay

HEp-2 cells, (originally derived from tumors grown inirradiated-cortisonised weanling rats that had been injected withepidermoid carcinoma tissue from a 56 year old male's larynx, but laterfound to be indistinguishable from HeLa cells by PCR DNA analysis), wereused for the culturing of genotype A, “Long” strain RSV. Flasks wereinoculated with RSV and viral stocks were collected once cytopathiceffect (CPE) was greater than 90%. Viral stocks in 25% sucrose mediawere snap frozen using liquid nitrogen to increase viral stability.Viral stock titers were quantified by tissue culture infectious dose 50%(TCID₅₀) using 8,000 cells per well and 3-fold viral dilutions across a96-well plate, cultured for 4 days. Viral stock titers were alsoquantified by a plaque forming unit assay, as described elsewhere.

Following extensive parameter testing, the final assay is run asfollows: HEp-2 cells are seeded into the inner 60 wells of a 96-wellplate at 8,000 cells per well in a volume of 50 μL using Growth Media(DMEM without phenol red, 1% L-Glut, 1% Penn/Strep, 1% nonessentialamino acids, 10% heat-inactivated FBS). 2-fold serial dilutions ofcontrol and test compounds are added to the wells in duplicate in atotal volume of 25 μL. Viral stock is then added to the wells at amultiplicity of infection (MOI) of 0.1 in a volume of 25 μL, bringingthe total volume of each well to 100 μL. The MOI is calculated using thePFU/mL, or TCID₅₀ if unavailable. Each 96-well plate has a controlcolumn of 6 wells with cells and virus but no compound (negativecontrol, max CPE), a column with cells but no compound or virus(positive control, minimum CPE), and a column with no cells or virus orcompound (background plate/reagent control). The control wells withcells but no virus are given an additional 25 μL of growth mediacontaining an equal quantity of sucrose as those wells receiving theviral stock in order to keep consistent in media and volume conditions.The outer wells of the plate are filled with 125 μL of moat media (DMEM,1% Penn/Strep) to act as a thermal and evaporative moat around the testwells. Following a 5-day incubation period, the plates are read usingATPlite (50 μL added per well), which quantifies the amount of ATP (ameasure of cell health) present in each well. Assay plates are readusing the Envision luminometer. In parallel, cytotoxicity is examined onan additional 96-well plate treated in an identical manner, butsubstituting the 25 μL of viral stock for 25 μL of growth media. Thesedata are used to calculate the EC₅₀ and CC₅₀ of each compound (Table 2).EC₅₀ ranges are as follows: A<0.4 μM; B 0.4-0.8 μM; C>0.8 μM and CC₅₀ranges are as follows: A>50 M; B 10-50 M; C<10 M.

TABLE 2 Summary of Activities for RSV-A Human RSV-A Human RSV-A Exam-(“Long” strain) CC₅₀ Exam- (“Long” strain) CC₅₀ ple EC₅₀ ATPlite pleEC₅₀ ATPlite  1 C A  2 C A  3 C A  4 C A  5 C A  6 C A   7a B A   7b C B 8 C A  9 C A  10a B A  10b C C  11 B A  12 B A  13 A A  14 A B  15 B A 16 B A  17 C A  18 C A  19 C A  20 C A  21 C A  22 C A  23 C A  24 B — 25 C A  26 C A  27 C A  28 C A  29 C A  30 C A  31 B A  32 B A  33 C A 34 B A  35 C A  36 B B  37 C A  38 C A  39 C A  40 C A  41 C A  42 B A 43 C A  44 C A  45 C A  46 C A  47 C A  48 C A  49 C A  50 C A  51 B A 52 A A  53 B A  54 A A  55 A A  56 C —  57 C A  58 C A  59 C A  60 C A 61 B A  62 C A  63 C A  64 C A  65 C A  66 B A  67 C A  68 C A  69 C A 70 C A  71 C A  72 C A  73 C A  74 C A  75 C A  76 C A  77 B A  78 C — 79 C A  80 C A  81 C A  82 B A  83 C A  84 C B  85 C —  86 C A  87 C B 88 C B  89 C B  90 C C  91 C —  92 C B  93 C B  94 C B  95 B —  96 C B 97 C A  98 C A  99 C B 100 C B 101 C B 102 C — 103 C B 104 C B 105 C A106 C C 107 C — 108 C — 109 C — 110 C — 111 C — 112 C — 113 B — 114 C —115 A — 116 C — 117 C — 118 C — 119 B — 120 A — 121 C — 122 C — 123 A — 124a A —  124b C —  125a A —  125b C —  126a A —  126b C — 127 A — 128B — 129 A — 130 B — 131 A — 132 A — 133 B — 134 C — 135 C — 136 A — 137C — 138 A — 139 A — 140 A — 141 C — 142 B — 143 A — 144 A — 145 B — 146C — 147 C — 148 C — 149 B — 150 A — 151 A — 152 A — 153 A — 154 A — 155A — 156 C — 157 A — 158 A — 159 A — 160 A — 161 C — 162 A — 163 C — 164A — 165 B — 166 C — 167 A — 168 A — 169 A — 170 C — 171 C — 172 C — 173C — 174 A — 175 A — 176 A — 177 C — 178 B — 179 A — 180 A — 181 A — 182A — 183 A — 184 B — 185 C — 186 C — 187 B — 188 C — 189 C — 190 C — 191C — 192 C — 193 C — 194 C — 195 C — 196 C — 197 C — 198 C — 199 C — 200B — 201 C — 202 C — 203 C — 204 C — 205 C — 206 C — 207 C — 208 C — 209C — 210 C — 211 C — 212 C — 213 C — 214 C — 215 C — 216 B — 217 B — 218C — 219 C — 220 C — 221 C — 222 C — 223 C — 224 C — 225 C — 226 C — 227C — 228 C — 229 C — 230 C — 231 A — 232 C — 233 C — 234 C — 235 C — 236C — 237 C — 238 C — 239 C — 240 C — 241 C — 242 A — 243 C — 244 C — 245A — 246 C — 247 C — 248 C — 249 C — 250 A — 251 A — 252 A — 253 A — 254C — 255 C — 256 C — 257 C — 258 C — 259 C — 260 C — 261 C — 262 C — 263B — 264 C — 265 C — 266 B — 267 C — 268 C — 269 C — 270 C — 271 C — 272A — 273 B — 274 C — 275 C — 276 B — 277 A — 278 A — 279 A — 280 A — 281A — 282 C — 283 C — 284 C — 285 A — 286 A — 287 C — 288 B — 289 A — 290C — 291 C — 292 A — 293 C — 294 A — 295 A — 296 C — 297 A — 298 C — 299A — 300 A — 301 A — 302 C — 303 A — 304 A — 305 A — 306 C — 307 C — 308C — 309 C — 310 C — 311 A — 312 B — 313 A — 314 A — 315 C — 316 C — 317A — 318 A — 319 C — 320 C — 321 A — 322 A — 323 A — 324 A — 325 A — 326B — 327 B — 328 C — 329 A — 330 A — 331 C — 332 C — 333 B — 334 A — 335A — 336 A — 337 A — 338 A — 339 A — 340 A — 341 A — 342 A — 343 C — 344C — 345 A — 346 A — 347 A — 348 A — 349 C — 350 B — 351 B — 352 — — 353C — 354 C —  355a A —  355b C — 356 B — 357 C — 358 A — 359 A — 360 A —361 A — 362 C — 363 C — 364 A — 365 B — 366 C — 367 C — 368 B — 369 C —370 C — 371 C — 372 C — 373 C — 374 C — 375 C — 376 C — 377 A — 378 C —379 C — 380 B — 381 C — 382 C — 383 A — 384 A — 385 A — 387 A — 388 A —389 A — 390 A — 393 — — 394 C — 395 C — 396 C — 399 A — 400 A — 401 A —402 A — 403 A — 404 A — 405 A — 406 A — 407 A — 408 C — 409 C — 410 C —411 C — 412 C — 413 C — 414 C — 415 C — 416 C — 417 C — 418 C — 419 B —420 A — 421 C — 422 B — 423 B — 424 C — 425 A — 426 C — 427 A — 428 A —429 A — 430 A — 431 A — 432 C — 433 A — 434 A — 435 C — 436 A — 437 A —438 B — 439 C — 440 B — 441 C — 442 A — 443 C — 444 A — 445 B — 446 A —447 B — 448 A — 449 C — 450 C — 451 B — 452 A — 453 A — 454 A — 455 A —456 C — 457 C — 458 A — 459 A — 460 A — 461 A — 462 C — 463 C — 464 A —465 B — 466 A — 467 A — 468 C — 469 A — 470 C — 471 A — 472 C — 473 A —474 A — 475 B — 476 B — 477 A — 478 A — 479 C — 480 C — 481 C — 482 C —483 C — 484 A — 485 C — 486 C — 487 C — 488 A — 489 C — 490 A — —

Methods for RSV-B Assay

HEp-2 cells, (originally derived from tumors grown inirradiated-cortisonised weanling rats that had been injected withepidermoid carcinoma tissue from a 56 year old male's larynx, but laterfound to be indistinguishable from HeLa cells by PCR DNA analysis), wereused for the culturing of genotype B, strain 9320. Flasks wereinoculated with RSV-B and viral stocks were collected once cytopathiceffect (CPE) was greater than 90%. Viral stocks in 25% sucrose mediawere snap frozen using liquid nitrogen to increase viral stability.Viral stock titers were quantified by tissue culture infectious dose 50%(TCID₅₀) using 8,000 cells per well and 5-fold viral dilutions across a96-well plate, cultured for 4 days. Viral stock titers were alsoquantified by a plaque forming unit assay, as described elsewhere.

The assay is run as follows: A549 cells (originally derived throughexplant culture from a 58 year old male's carcinomatous lung tissue) areseeded into the inner 60 wells of a 96-well plate at 3,000 cells perwell in a volume of 50 μL using A549 growth media (F-12K Media, 1%Penn/Strep, 1% nonessential amino acids, 10% heat-inactivated FBS).2-fold serial dilutions of control and test compounds are added to thewells in duplicate in a total volume of 25 μL. Viral stock is then addedto the wells at a multiplicity of infection (MOI) of 0.5 in a volume of25 μL, bringing the total volume of each well to 100 μL. The MOI iscalculated using the PFU/mL, or TCID₅₀ if unavailable. Each 96-wellplate has a control column of 6 wells with cells and virus but nocompound (negative control, max CPE), a column with cells but nocompound or virus (positive control, minimum CPE), and a column with nocells or virus or compound (background plate/reagent control). Thecontrol wells with cells but no virus are given an additional 25 μL ofgrowth media containing an equal quantity of sucrose as those wellsreceiving the viral stock in order to keep consistent in media andvolume conditions. The outer wells of the plate are filled with 125 μLof moat media (DMEM, 1% Penn/Strep) to act as a thermal and evaporativemoat around the test wells. 6 days post infection, the plates are readusing qPCR or ATP lite (50 μL added per well), which quantifies theamount of ATP (a measure of cell health) present in each well. Assayplates treated with APTlite are read using the Envision luminometer.These data are used to calculate the EC₅₀ of each compound (Table 3).EC₅₀ ranges are as follows: A<0.4 μM; B 0.4-0.8 μM; C>0.8 μM.

TABLE 3 Summary of Activities for RSV-B Exam- Human RSV-B Exam- HumanRSV-B ple EC₅₀ ple EC₅₀  7a C 95 C 108 C 120 B 123 B 124 A 125 B 127 A129 A 131 A 136 A 139 A 144 A 153 A 155 A 158 A 160 A 168 A 169 A 175 B179 A 224 A 242 A 245 B 250 A 251 A 252 A 253 A 263 B 268 B 269 B 272 A276 C 277 A 278 A 300 A 303 A 304 A 322 A 334 A 336 A 338 A 339 A 340 A341 A 351 B  355a A 358 A 364 B 377 A 385 A 387 A 388 A 403 A 407 A 429A

Methods for Combination Testing

Compounds were serially diluted 1.3-fold in DMSO across 7 columns orrows of a 96-well plate using a Well-Pro machine. By using a 1.3-folddilution, the base of the inhibition curve (˜3% viral inhibition)resides at one end of the dilution plate, while the opposite end of thedilution plate approaches the 90% viral inhibition point. This allowsfor maximum resolution in the assay.

FIG. 1 and Table 4 show respectively the plate layout and concentrationsof each drug as used in this assay. FIG. 1 is a graphical representationof the layout of drugs and the combination of compounds across 96-wellplates. The X-plate and Y-plate details the layout of the individualcompounds diluted out in DMSO, while the assay plate depicts thecombination of the compounds as they reside in the final assay plates,including location of viral infection and controls.

HEp-2 cells were seeded into wells of the assay plates at 8,000cells/well in 50 μL of Growth Media (DMEM without phenol red, 1% L-Glut,1% Penn/Strep, 1% nonessential amino acids, 10% heat-inactivated FBS).Compound and DMSO from both the X and respective Y plates were added tothe assay plate by first diluting each compound in Growth Media and thenadding 12.5 μL of diluted compound to the master plate for each compound(25 μL total). This represents a 400-fold dilution of compound from DMSOplate to the assay plate. Viral stock is then added to the wells at amultiplicity of infection (MOI) of 0.1 in a volume of 25 μL, bringingthe total volume of each well to 100 μL. The MOI is calculated using thePFU/mL. Each 96-well plate has a control column of 8 wells with cellsand virus but no compound (negative control, max CPE), and a column withcells but no compound or virus (positive control, minimum CPE). Thecontrol wells with cells but no virus are given an additional 25 μL ofGrowth Media containing an equal quantity of sucrose as those wellsreceiving the viral stock in order to keep consistent in media andvolume conditions (as our viral stocks are suspended in 25% sucrose).The outer wells of the plate are filled with 125 μL of moat media (DMEM,1% Penn/Strep) to act as a thermal and evaporative moat around the testwells. Each drug combination is run on 4×96-well plates inquadruplicate. Following a 5-day incubation period in a 37° C. CO2humidified incubator, the plates are read using ATPlite (50 μL added perwell), which quantifies the amount of ATP (a measure of cell health)present in each well. Assay plates are read using an Envisionluminometer. In parallel, cytotoxicity is examined on an additional96-well plate treated in an identical manner, but substituting the 25 μLof viral stock for 25 μL of growth media. The combinations were analyzedfor antagonism, additivity, or synergy using the Loewe additivity modeland quantified by the combination index (CI) using CalcuSyn softwarefrom Biosoft.

FIG. 2 is a graphical representation of the percent viral inhibition ofthe compounds or combinations of compounds at every individualconcentration or combination concentration tested. When no compound isgiven, there is 0% viral inhibition, while top concentrations ofcompounds given in combination reach or approach 100% viral inhibition.These data are used to calculate a combination index which determines ifcompounds are antagonistic, additive, or synergistic using the Loeweadditivity model. The results are presented in Table 5.

TABLE 5 Combination Index Values Avg. Combination Index (Cl) atCompounds EC₅₀ EC₇₅ EC₉₀ EC₉₅ Avg. Example 253 + Example 253 0.8 0.8 0.90.9 0.9 Example 253 + ALS-8112 0.7 0.6 0.5 0.4 0.6 Example 253 + AZ-270.8 0.6 0.5 0.4 0.6 Example 253 + GS5806 0.9 0.7 0.6 0.5 0.7 Example253 + Ribavirin 0.9 1.0 1.1 1.2 1.0 Example 253 + Palivizumab 0.8 0.80.7 0.6 0.7 Cl < 0.9 = synergy Cl > 1.1 = antagonism Cl 0.9-1.1 =additivity

Combinations of Example 253 and palivizumab, ribavirin, GS-5806, AZ-27,or ALS-8112 were additive to moderately synergistic.

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

1. A method of treating a human respiratory syncytial virus infection in a subject in need thereof, comprising administering to the subject a compound represented by Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: R₁ is selected from the group consisting of: 1) Hydrogen; 2) Halogen; 3) CN; 4) Optionally substituted —C₁-C₈ alkyl; and 5) Optionally substituted —C₁-C₈ alkyl —O—R₁₁; R₂ and R₅ are each independently selected from the group consisting of: 1) Hydrogen; and 2) Optionally substituted —C₁-C₈ alkyl; A is selected from the group consisting of: 1) Optionally substituted —C₃-C₁₂ cycloalkyl; 2) Optionally substituted —C₃-C₁₂ cycloalkenyl; 3) Optionally substituted 3- to 12-membered heterocycloalkyl; 4) Optionally substituted aryl; and 5) Optionally substituted heteroaryl; R₃ is hydrogen or R₁₁; R₄ is selected from the group consisting of: 1) Optionally substituted —C₃-C₁₂ cycloalkyl; 2) Optionally substituted —C₃-C₁₂ cycloalkenyl; 3) Optionally substituted 3- to 12-membered heterocyclyl; 4) Optionally substituted aryl; 5) Optionally substituted heteroaryl; 6) Optionally substituted aryl-O—; 7) Optionally substituted heteroaryl-O; 8) Optionally substituted aryl-C₁-C₄-alkyl; and 9) Optionally substituted heteroaryl-C₁-C₄-alkyl; each R₆ is the same or different and independently selected from hydrogen, halogen, hydroxyl, protected hydroxyl, cyano, amino, protected amino, nitro, optionally substituted —C₁-C₈ alkyl, optionally substituted —C₁-C₈ alkoxy, optionally substituted —NHC₁-C₈ alkyl, optionally substituted —S—(—C₁-C₈ alkyl), optionally substituted —SO₂—(—C₁-C₈ alkyl), -optionally substituted —SO₂—NH—(—C₁-C₈ alkyl), optionally substituted —NH—SO₂—(—C₁-C₈ alkyl), —CO₂R₁₂, —NR₁₃R₁₄, and —CO—NR₁₃R₁₄; R₁₁ and R₁₂ are each independently is selected from the group consisting of: 1) Optionally substituted —C₁-C₈ alkyl; 2) Optionally substituted —C₂-C₈ alkenyl; 3) Optionally substituted —C₂-C₈ alkynyl; 4) Optionally substituted —C₃-C₈ cycloalkyl; 5) Optionally substituted —C₃-C₈ cycloalkenyl; 6) Optionally substituted 3- to 8-membered heterocycloalkyl; 7) Optionally substituted aryl; and 8) Optionally substituted heteroaryl; R₁₃ and R₁₄ are each independently selected from hydrogen, optionally substituted —C₁-C₈-alkyl, optionally substituted —C₂-C₈-alkenyl, optionally substituted —C₂-C₈-alkynyl; optionally substituted —C₃-C₈-cycloalkyl, —C(O)R₁₂, —S(O)₂R₁₂, and —S(O)₂NHR₁₂, and optionally substituted —C₁-C₈-alkoxy; alternatively, R₁₃ and R₁₄ are taken together with the nitrogen they attached to form a heterocyclic ring; and n is 0, 1, 2, 3 or 4; and a second anti-respiratory syncytial virus agent, wherein the compound of Formula I and the second agent are administered in a combined amount which is therapeutically effective.
 2. The method of claim 1, wherein the compound of Formula (I) is represented by Formula Ia or Formula Ib,

or a pharmaceutically acceptable salt thereof.
 3. The method of claim 1, wherein A is selected from one of the following by removal of two hydrogen atoms:

wherein each of the above shown is optionally substituted when possible.
 4. The method of claim 1, wherein R₄ is selected from one of the following by removal of one hydrogen atom:

wherein each of the above shown is optionally substituted when possible.
 5. The method of claim 1, wherein R₄ is optionally substituted by 1 to 3 substituents independently selected from the group consisting of halo, —CH₃, —CF₃, —OCF₃, —CN, —NH₂, —OH, —CH₂N(CH₃)₂, —C(O)CH₃, optionally substituted —NH—(C₁-C₆)alkyl, optionally substituted —NH—(C₁-C₆)alkyl-(C₁-C₆)alkoxy, optionally substituted —SO₂—(C₁-C₆)alkyl, optionally substituted —SO₂—NH—(C₁-C₆)alkyl, optionally substituted —NH—SO₂—(C₁-C₆)alkyl, optionally substituted 3- to 12-membered heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted —C₁-C₈-alkyl, optionally substituted —C₁-C₈-alkenyl, optionally substituted —C₃-C₈-cycloalkyl, optionally substituted —C₃-C₈-cycloalkenyl, and optionally substituted —C₁-C₈-alkoxy.
 6. The method of claim 1, wherein R₄ is substituted by 1 to 3 substituents independently selected from the group consisting of CH₃, CN, fluoro, chloro, CH₃O—, CH₃C(O)—, CH₃OCH₂—, CH₃OCH₂CH₂O—, —CF₃, CF₃O—,


7. The method of claim 1, wherein the compound of Formula I is represented by IIa-1, IIa-2, IIb-1, or IIb-2, or a pharmaceutically acceptable salt thereof,

wherein R₂, R₃, R₄, R₅, R₆, n and A are as defined in claim
 1. 8. The method of claim 1, wherein the compound of Formula I is represented by Formula IV-1, IV-2, IV-3, or IV-4 or a pharmaceutically acceptable salt thereof,

wherein R₁, R₂, R₃, R₄, R₅, R₆, and n are as defined in claim
 1. 9. The method of claim 1, wherein the compound of Formula I is represented by Formula V-1, V-2, V-3, or V-4,

or a pharmaceutically acceptable salt thereof, wherein R₁, R₂, R₃, R₄, R₅, R₆, and n are as defined in claim
 1. 10. The method of claim 1, wherein the compound of Formula I is selected from the compounds set forth below or a pharmaceutically acceptable salt thereof: Example Structure 1

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11. The method of claim 1, wherein the second anti-respiratory syncytial virus agent is selected from the group consisting of an anti-RSV antibody, a fusion inhibitor, an N-protein inhibitor, a nucleoside or non-nucleoside RSV L polymerase inhibitor, an IMPDH inhibitor, an siRNA, and an interferon.
 12. The method of claim 11, wherein the second anti-respiratory syncytial virus agent is selected from the group consist of RSV-IGIV, palivizumab, motavizumab, MK-1654, I-cyclopropyl-3-[[1-(4-hydroxybutyl)benzimidazol-2-yl]methyl]imidazo[4,5-c]pyridin-2-one (BMS-433771), 4,4″-bis-{4,6-bis-[3-(bis-carbamoylmethyl-sulfamoyl)-phenylamino]-(1,3,5)triazin-2-ylamino}-biphenyl-2,2″-di sulfonic-acid (RFI-641), 4,4′-Bis[4,6-di[3-aminophenyl-N,N-bis(2-carbamoylethyl)-sulfonilimino]-1,3,5-triazine-2-ylamino]-biphenyl-2,2′-disulfonic acid, disodium salt (CL387626), 2-[[2-[[1-(2-aminoethyl)-4-piperidinyl]amino]-4-methyl-1H-benzimidazol-1-yl]-6-methyl-3-pyridinol (JNJ-2408068), 2-[[6-[[[2-(3-Hydroxypropyl)-5-methylphenyl]amino]methyl]-2-[[3-(morpholin-4-yl)propyl]amino]benzimidazol-1-yl]methyl]-6-methylpyridin-3-ol (TMC-353121), 5,5′-bis[1-(((5-amino-1H-tetrazolyl)imino)methyl)]2,2′,4″-methylidynetrisphenol (VP-14637, MDT-637), N-(2-hydroxyethyl)-4-methoxy-N-methyl-3-(6-methyl-[1,2,4]triazolo[3,4-a]phthalazin-3-yl)benzenesulfonamide (P13), 2-((2-((1-(2-aminoethyl)piperidin-4-yl)amino)-4-methyl-1H-benzo[d]imidazol-1-yl)methyl)-6-methylpyridin-3-ol (R170591), 1,4-bis(3-methylpyridin-4-yl)-1,4-diazepane (05), (R)-9b-(4-chlorophenyl)-1-(4-fluorobenzoyl)-2,3-dihydro-1H-imidazo[r,2′:1,2]pyrrolo[3,4-c]pyridin-5(9bH)-one (BTA9981), [2,2-bis(docosyloxyoxymethyl)propyl-5-acetaoamido-3,5-dideoxy-4,7,8,9-tetra-0-(sodium-oxysulfonyl)-D-glycero-D-galacto-2-nonulopyranosid]onate (MBX-300), BTA-C286, N-(2-((S)-2-(5-((S)-3-aminopyrrolidin-1-yl)-6-methylpyrazolo[1,5-a]pyrimidin-2-yl)piperidine-1-carbonyl)-4-chlorophenyl)methanesulfonamide (GS-5806), an anti-RSV nanobody, a peptide fusion inhibitor, (S)-1-(2-fluorophenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)urea (RSV-604), STP-92, iKT-041, 6-{4-[(biphenyl-2-ylcarbonyl) amino]benzoyl}-N-cyclopropyl-5,6-dihydro-4H-thieno[3,2-d][1]benzazepine-2-carboxamide (YM-53403). N-cyclopropyl-5-(4-(2-(pyrrolidin-1-yl)benzamido) benzoyl)-5,6,7,10-tetrahydrobenzo[b]cyclopenta[d]azepine-9-carboxamide, 6-(4-(2-(2-oxa-7-azaspiro[3.5]nonan-7-yl)nicotinamido)benzoyl)-N-cyclopropyl-5,6-dihydro-4H-benzo[b]thieno[2,3-d]azepine-2-carboxamide, 4-amino-8-(3-{[2-(3,4-dimethoxyphenyl)ethyl]amino}propyl)-6,6-dimethyl-2-(4-methyl-3-nitrophenyl)-1H-imidazo[4,5-h]-isoquinoline-7,9(6H,8H)-dione, AZ-27, ribavirin, 5-ethynyl-1-beta-D-ribofuranosylimidazole-4-carboxamide (EICAR), 4-hydroxy-3-beta-D-ribofuranosylpyrazole-5-carboxamide (pyrazofurin), 1-((2R,3R,4S,5R)-3,4-dihydroxy-5 (hydroxymethyl)tetrahydrofuran-2-yl)-1H-1,2,4-triazole-3-carboximidamide (Taribavirin, viramidine), (2R,3R,4R,5R)-5-(4-amino-2-oxopyrimidin-1-(2H)-yl)-2-(chloromethyl)-4-fluoro-2-((isobutyryloxy)methyl)tetrahydrofuran-3-yl isobutyrate, (2R,3R,4R,5R)-5-(4-amino-2-oxopyrimidin-1 (2H)-yl)-2-(chloromethyl)-4-fluoro-2(hydroxymethyl)tetrahydrofuran-3-yl isobutyrate, ((2R,3R,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-(chloromethyl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methyl triphosphate, 4-amino-1-((2R,3R,4R,5R)-5-(chloromethyl)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)-one, 1,3,4-thiadiazol-2-ylcyanamide (LY253963), tetrahydrofuran-3-yl-3-(3-(3-methoxy-4-(oxazol-5-yl)phenyl)ureido)benzylcarbamate (VX-497), (4E)-6-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-2-benzofuran-5-yl)-4-methylhex-4-enoic acid (Mycophenolic acid), 2-morpholin-4-ylethyl-(E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1H-2-benzofuran-5-yl)-4-methylhex-4-enoate (Mycophenolate Mofetil), a Type I interferon, a Type 2 interferon, a Type 3 interferon, a double stranded RNA oligonucleotide, 5-methyl-N-[4-(trifluoromethyl) phenyl]-isoxazole-4-carboxamide (leflumomide), N-(2-chloro-4-methylphenyl)-2-((1-(4-methoxyphenyl)-1H-benzo[d]imidazol-2-yl)thio)propanamide (JMN3-003), an intratracheal formulation of recombinant human CClO (CG-100), high titer, human immunoglobulin (RI-001), a non-neutralizing mAb against the G protein (mAb 131-2G), ALN-RSVO1, ALN-RSV02, Medi-559, Medi-534 and Medi-557, JNJ-53718678, AK-0529, RV521, BTA585, MIV-323, PC786, JNJ-64417184, ALS-8176, ALS-8112, ALX-0171, or a pharmaceutically acceptable salt of any of the foregoing.
 13. The method of claim 1, wherein the compound of Formula I or salt thereof and the second anti-respiratory syncytial virus agent are administered in a single composition or as separate compositions.
 14. A pharmaceutical composition comprising a compound represented by Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: R₁ is selected from the group consisting of: 1) Hydrogen; 2) Halogen; 3) CN; 4) Optionally substituted —C₁-C₈ alkyl; and 5) Optionally substituted —C₁-C₈ alkyl —O—R₁₁; R₂ and R₅ are each independently selected from the group consisting of: 1) Hydrogen; and 2) Optionally substituted —C₁-C₈ alkyl; A is selected from the group consisting of: 1) Optionally substituted —C₃-C₁₂ cycloalkyl; 2) Optionally substituted —C₃-C₁₂ cycloalkenyl; 3) Optionally substituted 3- to 12-membered heterocycloalkyl; 4) Optionally substituted aryl; and 5) Optionally substituted heteroaryl; R₃ is hydrogen or R₁₁; R₄ is selected from the group consisting of: 1) Optionally substituted —C₃-C₁₂ cycloalkyl; 2) Optionally substituted —C₃-C₁₂ cycloalkenyl; 3) Optionally substituted 3- to 12-membered heterocyclyl; 4) Optionally substituted aryl; 5) Optionally substituted heteroaryl; 6) Optionally substituted aryl-O—; 7) Optionally substituted heteroaryl-O; 8) Optionally substituted aryl-C₁-C₄-alkyl; and 9) Optionally substituted heteroaryl-C₁-C₄-alkyl; each R₆ is the same or different and independently selected from hydrogen, halogen, hydroxyl, protected hydroxyl, cyano, amino, protected amino, nitro, optionally substituted —C₁-C₈ alkyl, optionally substituted —C₁-C₈ alkoxy, optionally substituted —NHC₁-C₈ alkyl, optionally substituted —S—(—C₁-C₈ alkyl), optionally substituted —SO₂—(—C₁-C₈ alkyl), -optionally substituted —SO₂—NH—(—C₁-C₈ alkyl), optionally substituted —NH—SO₂—(—C₁-C₈ alkyl), —CO₂R₁₂, —NR₁₃R₁₄, and —CO—NR₁₃R₁₄; R₁₁ and R₁₂ are each independently is selected from the group consisting of: 1) Optionally substituted —C₁-C₈ alkyl; 2) Optionally substituted —C₂-C₈ alkenyl; 3) Optionally substituted —C₂-C₈ alkynyl; 4) Optionally substituted —C₃-C₈ cycloalkyl; 5) Optionally substituted —C₃-C₈ cycloalkenyl; 6) Optionally substituted 3- to 8-membered heterocycloalkyl; 7) Optionally substituted aryl; and 8) Optionally substituted heteroaryl; R₁₃ and R₁₄ are each independently selected from hydrogen, optionally substituted —C₁-C₈-alkyl, optionally substituted —C₂-C₈-alkenyl, optionally substituted —C₂-C₈-alkynyl; optionally substituted —C₃-C₅-cycloalkyl, —C(O)R₁₂, —S(O)₂R₁₂, and —S(O)₂NHR₁₂, and optionally substituted —C₁-C₈-alkoxy; alternatively, R₁₃ and R₁₄ are taken together with the nitrogen they attached to form a heterocyclic ring; and n is 0, 1, 2, 3 or 4; a second anti-respiratory syncytial virus agent; and a pharmaceutically acceptable carrier or excipient.
 15. The pharmaceutical composition of claim 14, wherein the compound of Formula (I) is represented by Formula Ia or Formula Ib,

or a pharmaceutically acceptable salt thereof.
 16. The pharmaceutical composition of claim 14, wherein A is selected from one of the following by removal of two hydrogen atoms:

wherein each of the above shown is optionally substituted when possible.
 17. The pharmaceutical composition of claim 14, wherein R₄ is selected from one of the following by removal of one hydrogen atom:

wherein each of the above shown is optionally substituted when possible.
 18. The pharmaceutical composition of claim 14, wherein R₄ is optionally substituted by 1 to 3 substituents independently selected from the group consisting of halo, —CH₃, —CF₃, —OCF₃, —CN, —NH₂, —OH, —CH₂N(CH₃)₂, —C(O)CH₃, optionally substituted —NH—(C₁-C₆)alkyl, optionally substituted —NH—(C₁-C₆)alkyl-(C₁-C₆)alkoxy, optionally substituted —SO₂—(C₁-C₆)alkyl, optionally substituted —SO₂—NH—(C₁-C₆)alkyl, optionally substituted —NH—SO₂—(C₁-C₆)alkyl, optionally substituted 3- to 12-membered heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted —C₁-C₈-alkyl, optionally substituted —C₁-C₈-alkenyl, optionally substituted —C₃-C₈-cycloalkyl, optionally substituted —C₃-C₈-cycloalkenyl, and optionally substituted —C₁-C₈-alkoxy.
 19. The pharmaceutical composition of claim 14, wherein R₄ is substituted by 1 to 3 substituents independently selected from the group consisting of CH₃, CN, fluoro, chloro, CH₃O—, CH₃C(O)—, CH₃CH₂—, CH₃OCH₂CH₂O—, —CF₃, CF₃O—,


20. The pharmaceutical composition of claim 14, wherein the compound of Formula I is represented by Formula IIa-1, IIa-2, IIb-1, or IIb-2, or a pharmaceutically acceptable salt thereof,

wherein R₂, R₃, R₄, R₅, R₆, n and A are as defined in claim
 1. 21. The pharmaceutical composition of claim 14, wherein the compound of Formula I is represented by Formula IV-1, IV-2, IV-3, or IV-4 or a pharmaceutically acceptable salt thereof,

wherein R₁, R₂, R₃, R₄, R₅, R₆, and n are as defined in claim
 1. 22. The pharmaceutical composition of claim 14, wherein the compound of Formula I is represented by Formula V-1, V-2, V-3, or V-4,

or a pharmaceutically acceptable salt thereof, wherein R₁, R₂, R₃, R₄, R₅, R₆, and n are as defined in claim
 1. 23. The pharmaceutical composition of claim 14, wherein the compound of Formula I is selected from the compounds set forth below or a pharmaceutically acceptable salt thereof: Ex- am- ple Structure  1

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24. The pharmaceutical composition of claim 23, wherein the compound of Formula I is Example 253 or a pharmaceutically acceptable salt thereof.
 25. The pharmaceutical composition of claim 14, wherein the second anti-respiratory syncytial virus agent is selected from the group consisting of an anti-RSV antibody, a fusion protein inhibitor, an N-protein inhibitor, a RSV polymerase inhibitor, an IMPDH inhibitor, and an interferon.
 26. The pharmaceutical composition of claim 25, wherein the second anti-respiratory syncytial virus agent is selected from the group consist of RSV-IGIV, palivizumab, motavizumab, MK-1654, I-cyclopropyl-3-[[1-(4-hydroxybutyl)benzimidazol-2-yl]methyl]imidazo[4,5-c]pyridin-2-one (BMS-433771), 4,4″-bis-{4,6-bis-[3-(bis-carbamoylmethyl-sulfamoyl)-phenylamino]-(1,3,5)triazin-2-ylamino}-biphenyl-2,2″-di sulfonic-acid (RFI-641), 4,4′-Bis[4,6-di[3-aminophenyl-N,N-bis(2-carbamoylethyl)-sulfonilimino]-1,3,5-triazine-2-ylamino]-biphenyl-2,2′-disulfonic acid, disodium salt (CL387626), 2-[[2-[[1-(2-aminoethyl)-4-piperidinyl]amino]-4-methyl-1H-benzimidazol-1-yl]-6-methyl-3-pyridinol (JNJ-2408068), 2-[[6-[[[2-(3-Hydroxypropyl)-5-methylphenyl]amino]methyl]-2-[[3-(morpholin-4-yl)propyl]amino]benzimidazol-1-yl]methyl]-6-methylpyridin-3-ol (TMC-353121), 5,5′-bis[1-(((5-amino-1H-tetrazolyl)imino)methyl)]2,2′,4″-methylidynetrisphenol (VP-14637, MDT-637), N-(2-hydroxyethyl)-4-methoxy-N-methyl-3-(6-methyl-[1,2,4]triazolo[3,4-a]phthalazin-3-yl)benzenesulfonamide (P13), 2-((2-((1-(2-aminoethyl)piperidin-4-yl)amino)-4-methyl-1H-benzo[d]imidazol-1-yl)methyl)-6-methylpyridin-3-ol (R170591), 1,4-bis(3-methylpyridin-4-yl)-1,4-diazepane (05), (R)-9b-(4-chlorophenyl)-1-(4-fluorobenzoyl)-2,3-dihydro-1H-imidazo[r,2′:1,2]pyrrolo[3,4-c]pyridin-5(9bH)-one (BTA9981), [2,2-bis(docosyloxyoxymethyl)propyl-5-acetaoamido-3,5-dideoxy-4,7,8,9-tetra-0-(sodium-oxysulfonyl)-D-glycero-D-galacto-2-nonulopyranosid]onate (MBX-300), BTA-C286, N-(2-((S)-2-(5-((S)-3-aminopyrrolidin-1-yl)-6-methylpyrazolo[1,5-a]pyrimidin-2-yl)piperidine-1-carbonyl)-4-chlorophenyl)methanesulfonamide (GS-5806), an anti-RSV nanobody, a peptide fusion inhibitor, (S)-1-(2-fluorophenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)urea (RSV-604), STP-92, iKT-041, 6-{4-[(biphenyl-2-ylcarbonyl) amino]benzoyl}-N-cyclopropyl-5,6-dihydro-4H-thieno[3,2-d][1]benzazepine-2-carboxamide (YM-53403). N-cyclopropyl-5-(4-(2-(pyrrolidin-1-yl)benzamido) benzoyl)-5,6,7,10-tetrahydrobenzo[b]cyclopenta[d]azepine-9-carboxamide, 6-(4-(2-(2-oxa-7-azaspiro[3.5]nonan-7-yl)nicotinamido)benzoyl)-N-cyclopropyl-5,6-dihydro-4H-benzo[b]thieno[2,3-d]azepine-2-carboxamide, 4-amino-8-(3-{[2-(3,4-dimethoxyphenyl)ethyl]amino}propyl)-6,6-dimethyl-2-(4-methyl-3-nitrophenyl)-1H-imidazo[4,5-h]-isoquinoline-7,9(6H,8H)-dione, AZ27, ribavirin, 5-ethynyl-1-beta-D-ribofuranosylimidazole-4-carboxamide (EICAR), 4-hydroxy-3-beta-D-ribofuranosylpyrazole-5-carboxamide (pyrazofurin), 1-((2R,3R,4S,5R)-3,4-dihydroxy-5 (hydroxymethyl)tetrahydrofuran-2-yl)-1H-1,2,4-triazole-3-carboximidamide (Taribavirin, viramidine), (2R,3R,4R,5R)-5-(4-amino-2-oxopyrimidin-1-(2H)-yl)-2-(chloromethyl)-4-fluoro-2-((isobutyryloxy)methyl)tetrahydrofuran-3-yl isobutyrate, (2R,3R,4R,5R)-5-(4-amino-2-oxopyrimidin-1 (2H)-yl)-2-(chloromethyl)-4-fluoro-2(hydroxymethyl)tetrahydrofuran-3-yl isobutyrate, ((2R,3R,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-(chloromethyl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl) methyl triphosphate, 4-amino-1-((2R,3R,4R,5R)-5-(chloromethyl)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)-one, 1,3,4-thiadiazol-2-ylcyanamide (LY253963), tetrahydrofuran-3-yl-3-(3-(3-methoxy-4-(oxazol-5-yl)phenyl)ureido)benzylcarbamate (VX-497), (4E)-6-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-2-benzofuran-5-yl)-4-methylhex-4-enoic acid (Mycophenolic acid), 2-morpholin-4-ylethyl-(E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1H-2-benzofuran-5-yl)-4-methylhex-4-enoate (Mycophenolate Mofetil), a Type I interferon, a Type 2 interferon, a Type 3 interferon, a double stranded RNA oligonucleotide, 5-methyl-N-[4-(trifluoromethyl) phenyl]-isoxazole-4-carboxamide (leflumomide), N-(2-chloro-4-methylphenyl)-2-((1-(4-methoxyphenyl)-1H-benzo[d]imidazol-2-yl)thio)propanamide (JMN3-003), an intratracheal formulation of recombinant human CClO (CG-100), high titer, human immunoglobulin (RI-001), a non-neutralizing mAb against the G protein (mAb 131-2G), ALN-RS VOI, ALN-RSV 02, Medi-559, Medi-534 and Medi-557, JNJ-53718678, AK-0529, RV521, BTA585, MIV-323, PC786, JNJ-64417184, ALS-8176, ALS-8112, ALX-0171, or a pharmaceutically acceptable salt of any of the foregoing. 